Glycosidase inhibitors

ABSTRACT

Novel compounds of formula (I) 
     
       
         
         
             
             
         
       
     
     wherein R 1  to R 4  and X have the meaning according to the claims, are glucosidase inhibitors, and can be employed, inter alia, for the treatment of Alzheimer&#39;s disease.

The present invention relates to compounds of formula (I)

wherein R¹ to R⁴ and X have the meaning according to the claims, and/orphysiologically acceptable salts thereof. The compounds of formula (I)can be used as glycosidase inhibitors. Objects of the invention are alsopharmaceutical compositions comprising the compounds of formula (I), andthe use of the compounds of formula (I) for the treatment of Alzheimer'sdisease.

A wide range of cellular proteins, both nuclear and cytoplasmic, arepost-translationally modified by the addition of the monosaccharide2-acetamido-2-deoxy-β-D-glucopyranoside (β-N-acetyl glucosamine) whichis attached via an O-glycosidic linkage. This modification is generallyreferred to as O-linked N-acetylglucosamine or O-GlcNAc. The enzymeresponsible for post-translationally linking β-N-acetylglucosamine(GlcNAc) to specific serine and threonine residues of numerousnucleocytoplasmic proteins is O-GlcNAc transferase (OGTase). A secondenzyme, known as O-GlcNAcase, removes this post-translationalmodification to liberate proteins making the O-GlcNAc-modification adynamic cycle occurring several times during the lifetime of a protein.

O-GlcNAc-modified proteins regulate a wide range of vital cellularfunctions including, for example, transcription, proteasomal degradationand cellular signaling. O-GlcNAc is also found on many structuralproteins. For example, it has been found on a number of cytoskeletalproteins, including neurofilament proteins, synapsins, synapsin-specificclathrin assembly protein AP-3 and Ankyrin-G. O-GlcNAc modification hasbeen found to be abundant in the brain. It has also been found onproteins clearly implicated in the etiology of several diseasesincluding Alzheimer's disease (AD) and cancer.

For example, it is well established that AD and a number of relatedtauopathies including Downs' syndrome, Pick's disease, Niemann-Pick TypeC disease and amyotrophic lateral sclerosis (ALS) are characterized, inpart, by the development of neurofibrillary tangles (NFTs). These NFTsare aggregates of paired helical filaments (PHFs) and are composed of anabnormal form of the cytoskeletal protein “tau”. Normally, taustabilizes a key cellular network of microtubules that is essential fordistributing proteins and nutrients within neurons. In AD patients,however, tau becomes hyperphosphorylated, disrupting its normalfunction, forming PHFs and ultimately aggregating to form NFTs. Sixisoforms of tau are found in the human brain. In AD patients, all sixisoforms of tau are found in NFTs, and all are markedlyhyperphosphorylated. Tau in healthy brain tissue bears only 2 or 3phosphate groups, whereas those found in the brains of AD patients bear,on average, 8 phosphate groups. A clear parallel between NFT levels inthe brains of AD patients and the severity of dementia strongly supportsa key role for tau dysfunction in AD. The precise causes of thishyperphosphorylation of tau remain elusive. Accordingly, considerableeffort has been dedicated toward: a) elucidating the molecularphysiological basis of tau hyperphosphorylation; and b) identifyingstrategies that could limit tau hyperphosphorylation in the hope thatthese might halt, or even reverse, the progression of Alzheimer'sdisease. Several lines of evidence suggest that up-regulation of anumber of kinases may be involved in hyperphosphorylation of tau,although very recently, an alternative basis for thishyperphosphorylation has been advanced.

In particular, it has recently emerged that phosphate levels of tau areregulated by the levels of O-GlcNAc on tau. The presence of O-GlcNAc ontau has stimulated studies that correlate O-GlcNAc levels with tauphosphorylation levels. The recent interest in this field stems from theobservation that O-GlcNAc modification has been found to occur on manyproteins at amino acid residues that are also known to bephosphorylated. Consistent with this observation, it has been found thatincreases in phosphorylation levels result in decreased O-GlcNAc levelsand conversely, increased O-GlcNAc levels correlate with decreasedphosphorylation levels. This reciprocal relationship between O-GlcNAcand phosphorylation has been termed the “Yin-Yang hypothesis” and hasgained strong biochemical support by the recent discovery that theenzyme OGTase forms a functional complex with phosphatases that act toremove phosphate groups from proteins. Like phosphorylation, O-GlcNAc isa dynamic modification that can be removed and reinstalled several timesduring the lifespan of a protein. Suggestively, the gene encodingO-GlcNAcase has been mapped to a chromosomal locus that is linked to AD.Hyperphosphorylated tau in human AD brains has markedly lower levels ofO-GlcNAc than are found in healthy human brains. Very recently, it hasbeen shown that O-GlcNAc levels of soluble tau protein from human brainsaffected with AD are markedly lower than those from healthy brain.Furthermore, PHF from diseased brain was suggested to lack completelyany O-GlcNAc modification whatsoever. The molecular basis of thishypoglycosylation of tau is not known, although it may stem fromincreased activity of kinases and/or dysfunction of one of the enzymesinvolved in processing O-GlcNAc. Supporting this latter view, in bothPC-12 neuronal cells and in brain tissue sections from mice, anonselective N-acetylglucosaminidase inhibitor was used to increase tauO-GlcNAc levels, whereupon it was observed that phosphorylation levelsdecreased. The implication of these collective results is that bymaintaining healthy O-GlcNAc levels in AD patients, such as byinhibiting the action of O-GlcNAcase (OGA), one should be able to blockhyperphosphorylation of tau and all of the associated effects of tauhyperphosphorylation, including the formation of NFTs and downstreameffects. However, because the proper functioning of the lysosomalβ-hexosaminidases is critical, any potential therapeutic interventionfor the treatment of AD that blocks the action of O-GlcNAcase would haveto avoid the concomitant inhibition of both lysosomal hexosaminidases Aand B.

Consistent with the known properties of the hexosamine biosyntheticpathway, the enzymatic properties of O-GlcNAc transferase (OGTase), andthe reciprocal relationship between O-GlcNAc and phosphorylation, it hasbeen shown that decreased glucose availability in brain leads to tauhyperphosphorylation. The gradual impairment of glucose transport andmetabolism leads to decreased O-GlcNAc and hyperphosphorylation of tau(and other proteins). Accordingly, the inhibition of O-GlcNAcase shouldcompensate for the age-related impairment of glucose metabolism withinthe brains of health individuals as well as patients suffering from ADor related neurodegenerative diseases.

These results suggest that a malfunction in the mechanisms regulatingtau O-GlcNAc levels may be vitally important in the formation of NFTsand associated neurodegeneration. Good support for blocking tauhyperphosphorylation as a therapeutically useful intervention comes fromrecent studies showing that when transgenic mice harboring human tau aretreated with kinase inhibitors, they do not develop typical motordefects and, in another case, show decreased levels of insoluble tau.These studies provide a clear link between lowering tau phosphorylationlevels and alleviating AD-like behavioral symptoms in a murine model ofthis disease.

There is also a large body of evidence indicating that increased levelsof O-GlcNAc protein modification provides protection against pathogeniceffects of stress in cardiac tissue, including stress caused byischemia, hemorrhage, hypervolemic shock, and calcium paradox. Forexample, activation of the hexosamine biosynthetic pathway (HBP) byadministration of glucosamine has been demonstrated to exert aprotective effect in animal models of ischemia/reperfusion, traumahemorrhage, hypervolemic shock and calcium paradox. Moreover, strongevidence indicates that these cardioprotective effects are mediated byelevated levels of protein O-GlcNAc modification. There is also evidencethat the O-GlcNAc modification plays a role in a variety ofneurodegenerative diseases, including Parkinson's disease andHuntington's disease.

Humans have three genes encoding enzymes that cleave terminalβ-N-acetyl-glucosamine residues from glycoconjugates. The first of theseencodes the enzymeO-glycoprotein-2-acetamido-2-deoxy-β-D-glucopyranosidase (O-GlcNAcase).O-GlcNAcase is a member of family 84 of glycoside hydrolases.O-GlcNAcase acts to hydrolyze O-GlcNAc off of serine and threonineresidues of post-translationally modified proteins. Consistent with thepresence of O-GlcNAc on many intracellular proteins, the enzymeO-GlcNAcase appears to have a role in the etiology of several diseasesincluding type II diabetes, AD and cancer. Although O-GlcNAcase waslikely isolated earlier on, about 20 years elapsed before itsbiochemical role in acting to cleave O-GlcNAc from serine and threonineresidues of proteins was understood. More recently O-GlcNAcase has beencloned, partially characterized, and suggested to have additionalactivity as a histone acetyltransferase.

However, a major challenge in developing inhibitors for blocking thefunction of mammalian glycosidases, including O-GlcNAcase, is the largenumber of functionally related enzymes present in tissues of highereukaryotes. Accordingly, the use of non-selective inhibitors in studyingthe cellular and organismal physiological role of one particular enzymeis complicated because complex phenotypes arise from the concomitantinhibition of such functionally related enzymes. In the case ofβ-N-acetylglucosaminidases, existing compounds that act to blockO-GlcNAcase function are non-specific and act potently to inhibit thelysosomal β-hexosaminidases.

Low molecular weight OGA inhibitors are disclosed in the internationalapplication WO 2008/025170, WO 2011/140640, WO 2012/061927, WO2012/062157, WO 2012/083435, which are hereby incorporated by reference.There is still a need for low molecular weight molecules thatselectively inhibit OGA.

The invention had the object of finding novel compounds having valuableproperties, in particular those which can be used for the preparation ofmedicaments.

It has been surprisingly found that the compounds according to theinvention and salts thereof have very valuable pharmacologicalproperties. In particular, they act as glycosidase inhibitors. Theinvention relates to compounds of formula (I)

wherein

-   R¹ denotes Y, COA, COOA, COO—(CH₂)_(n)—Ar, COO—(CH₂)_(n)-Cyc;-   R², R³ denote independently from one another Y or SO₂Y;-   R⁴ denotes Hal, Y, OY, OCOOY, COOY, CONYY, NHCOY, SO₂Y, CN, NYY,    NYOY, N═N⁺═N⁻, CAr₃, (CH₂)_(n)—Ar, O—(CH₂)_(n)—Ar, NY—(CH₂)_(n)—Ar,    NY—(CH₂)_(n)-Cyc, NY—(CH₂)_(n)-Het,

-   R⁵ denotes (CH₂)_(n)—Ar, (CH₂)_(n)-Cyc, (CH₂)_(n)-Het,    (CH₂)_(n)—O—Ar, (CH₂)_(n)—CY(OH)—Ar, (CH₂)_(n)—CO—Ar or    (CH₂)_(n)—NY—Ar;-   X denotes CH₂, CO or CH(OH);-   Y denotes H or A;-   A denotes unbranched or branched alkyl having 1-10C atoms,    -   in which 1-7H atoms can be replaced independently from one        another by Hal and/or in which one CH₂ group can be replaced by        a —CH═CH— group;-   Cyc denotes cycloalkyl having 3-7C atoms,    -   in which 1-4H atoms can be replaced independently from one        another by Hal and/or which can be substituted by Ar;-   Ar denotes an unsaturated or aromatic mono- or bicyclic carbocycle    having 3-12 C atoms,    -   which can be substituted by at least one substituent selected        from the group of Hal, A, (CY₂)_(n)—OY, (CY₂)_(n)—NYY, COOY,        CONYY, NHCOY, SO₂Y, CN and phenoxy;-   Het denotes an unsaturated or aromatic mono-, bi- or tricyclic    heterocycle having 1-12 C atoms and 1-4 N atoms,    -   which can be substituted by at least one substituent selected        from the group of Hal, A, (CY₂)_(n)—OY, (CY₂)_(n)—NYY, COOY,        CONYY, NHCOY, SO₂Y, SO₂Ar, CN and thiophenyl;-   Hal denotes F, Cl, Br or I;-   m denotes 1, 2 or 3; and-   n denotes 0, 1, 2, 3, 4, 5 or 6;-   and/or physiologically acceptable salts thereof.

In particular, the invention relates to a compound of formula (I)

wherein

-   R¹ denotes Y, COA, COOA, COO—(CH₂)_(n)—Ar, COO—(CH₂)_(n)-Cyc;-   R², R³ denote independently from one another Y or SO₂Y;-   R⁴ denotes Cl, Br, I, COOY, SO₂Y, CN, CAr₃, (CH₂)_(m)—Ar,

-   R⁵ denotes (CH₂)_(n)—Ar, (CH₂)_(n)-Cyc, (CH₂)_(n)-Het,    (CH₂)_(n)—O—Ar, (CH₂)_(n)—CY(OH)—Ar, (CH₂)_(n)—CO—Ar or    (CH₂)_(n)—NY—Ar;-   X denotes CH₂, CO or CH(OH);-   Y denotes H or A;-   A denotes unbranched or branched alkyl having 1-10C atoms,    -   in which 1-7H atoms can be replaced independently from one        another by Hal and/or in which one CH₂ group can be replaced by        a —CH═CH— group;-   Cyc denotes cycloalkyl having 3-7C atoms,    -   in which 1-4H atoms can be replaced independently from one        another by Hal and/or which can be substituted by Ar;-   Ar denotes an unsaturated or aromatic mono- or bicyclic carbocycle    having 3-12 C atoms,    -   which can be substituted by at least one substituent selected        from the group of Hal, A, (CY₂)_(n)—OY, (CY₂)_(n)—NYY, COOY,        CONYY, NHCOY, SO₂Y, CN and phenoxy;-   Het denotes an unsaturated or aromatic mono-, bi- or tricyclic    heterocycle having 1-12

C atoms and 1-4 N atoms,

-   -   which can be substituted by at least one substituent selected        from the group of Hal, A, (CY₂)_(n)—OY, (CY₂)_(n)—NYY, COOY,        CONYY, NHCOY, SO₂Y, SO₂Ar, CN and thiophenyl;

-   Hal denotes F, Cl, Br or I;

-   m denotes 1, 2 or 3; and

-   n denotes 0, 1, 2, 3, 4, 5 or 6;

-   and/or a physiologically acceptable salt thereof.

In the meaning of the present invention, the compound is defined toinclude pharmaceutically usable derivatives, solvates, prodrugs,tautomers, enantiomers, racemates and stereoisomers thereof, includingmixtures thereof in all ratios.

The term “pharmaceutically usable derivatives” is taken to mean, forexample, the salts of the compounds according to the invention and alsoso-called prodrug compounds. The term “solvates” of the compounds istaken to mean adductions of inert solvent molecules onto the compounds,which are formed owing to their mutual attractive force. Solvates are,for example, mono- or dihydrates or alkoxides. The invention alsocomprises solvates of salts of the compounds according to the invention.The term “prodrug” is taken to mean compounds according to the inventionwhich have been modified by means of, for example, alkyl or acyl groups,sugars or oligopeptides and which are rapidly cleaved in the organism toform the effective compounds according to the invention. These alsoinclude biodegradable polymer derivatives of the compounds according tothe invention, as described, for example, in Int. J. Pharm. 115, 61-67(1995). It is likewise possible for the compounds of the invention to bein the form of any desired prodrugs such as, for example, esters,carbonates, carbamates, ureas, amides or phosphates, in which cases theactually biologically active form is released only through metabolism.Any compound that can be converted in-vivo to provide the bioactiveagent (i.e. compounds of the invention) is a prodrug within the scopeand spirit of the invention. Various forms of prodrugs are well known inthe art and are described (e.g. Wermuth C G et al., Chapter 31: 671-696,The Practice of Medicinal Chemistry, Academic Press 1996; Bundgaard H,Design of Prodrugs, Elsevier 1985; Bundgaard H, Chapter 5: 131-191, ATextbook of Drug Design and Development, Harwood Academic Publishers1991). Said references are incorporated herein by reference. It isfurther known that chemical substances are converted in the body intometabolites which may where appropriate likewise elicit the desiredbiological effect—in some circumstances even in more pronounced form.Any biologically active compound that was converted in-vivo bymetabolism from any of the compounds of the invention is a metabolitewithin the scope and spirit of the invention.

The compounds of the invention may be present in the form of theirdouble bond isomers as pure E or Z isomers, or in the form of mixturesof these double bond isomers. Where possible, the compounds of theinvention may be in the form of the tautomers, such as keto-enoltautomers. All stereoisomers of the compounds of the invention arecontemplated, either in a mixture or in pure or substantially pure form.The compounds of the invention can have asymmetric centers at any of thecarbon atoms. Consequently, they can exist in the form of theirracemates, in the form of the pure enantiomers and/or diastereomers orin the form of mixtures of these enantiomers and/or diastereomers. Themixtures may have any desired mixing ratio of the stereoisomers. Thus,for example, the compounds of the invention which have one or morecenters of chirality and which occur as racemates or as diastereomermixtures can be fractionated by methods known per se into their opticalpure isomers, i.e. enantiomers or diastereomers. The separation of thecompounds of the invention can take place by column separation on chiralor non-chiral phases or by re-crystallization from an optionallyoptically active solvent or with use of an optically active acid or baseor by derivatization with an optically active reagent such as, forexample, an optically active alcohol, and subsequent elimination of theradical.

The invention also relates to the use of mixtures of the compoundsaccording to the invention, for example mixtures of two diastereomers,for example in the ratio 1:1, 1:2, 1:3, 1:4, 1:5, 1:10, 1:100 or 1:1000.These are particularly preferably mixtures of stereoisomeric compounds.

The nomenclature as used herein for defining compounds, especially thecompounds according to the invention, is in general based on the rulesof the IUPAC-organization for chemical compounds and especially organiccompounds. The terms indicated for explanation of the above compounds ofthe invention always, unless indicated otherwise in the description orin the claims, have the following meanings:

The term “unsubstituted” means that the corresponding radical, group ormoiety has no substituents. The term “substituted” means that thecorresponding radical, group or moiety has one or more substituents.Where a radical has a plurality of substituents, and a selection ofvarious substituents is specified, the substituents are selectedindependently of one another and do not need to be identical. Eventhough a radical has a plurality of a specific-designated substituent(e.g. Ar₃ or YY) the expression of such substituent may differ from eachother (e.g. methyl and ethyl). It shall be understood accordingly that amultiple substitution by any radical of the invention may involveidentical or different radicals. Hence, if individual radicals occurseveral times within a compound, the radicals adopt the meaningsindicated, independently of one another. In case of a multiplesubstitution, the radical could be alternatively designated with R′, R″,R′″ etc.

The terms “alkyl” or “A” refer to acyclic saturated or unsaturatedhydrocarbon radicals, which may be branched or straight-chain andpreferably have 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 carbon atoms, i.e.C₁-C₁₀-alkanyls. Examples of suitable alkyl radicals are methyl, ethyl,n-propyl, isopropyl, 1,1-, 1,2- or 2,2-dimethylpropyl, 1-ethylpropyl,1-ethyl-1-methylpropyl, 1-ethyl-2-methylpropyl, 1,1,2- or1,2,2-trimethylpropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, 1-, 2-or 3-methylbutyl, 1,1-, 1,2-, 1,3-, 2,2-, 2,3- or 3,3-dimethylbutyl, 1-or 2-ethylbutyl, n-pentyl, iso-pentyl, neo-pentyl, tert-pentyl, 1-, 2-,3- or -methyl-pentyl, n-hexyl, 2-hexyl, isohexyl, n-heptyl, n-octyl,n-nonyl, n-decyl, n-undecyl, n-dodecyl, n-tetradecyl, n-hexadecyl,n-octadecyl, n-icosanyl, n-docosanyl.

In a preferred embodiment of the invention, A denotes unbranched orbranched alkyl having 1-10C atoms, in which 1-7H atoms may be replacedindependently from one another by Hal and/or in which one CH₂ group canbe replaced by a —CH═CH— group. A more preferred embodiment of A denotesunbranched or branched alkyl having 1-6C atoms, in which 1-4 atoms maybe replaced independently from one another by Hal. In a most preferredembodiment of the invention, A denotes unbranched or branched alkylhaving 1-4C atoms, in which 1-3H atoms can be replaced independentlyfrom one another by Hal. It is highly preferred that A denotesunbranched or branched alkyl having 1-4C atoms, in which 1-3H atoms canbe replaced independently from one another by F and/or Cl. Particularlypreferred are C₁₋₄-alkyl. A C₁₋₄-alkyl radical is for example a methyl,ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, sec-butyl,tert-butyl, fluoromethyl, difluoromethyl, trifluoromethyl,pentafluoroethyl, 1,1,1-trifluoroethyl or bromomethyl, especiallymethyl, ethyl, propyl or trifluoromethyl. It shall be understood thatthe respective denotation of A is independently of one another in anyradical of the invention.

The terms “cycloalkyl” or “Cyc” for the purposes of this inventionrefers to saturated and partially unsaturated non-aromatic cyclichydrocarbon groups/radicals, having 1 to 3 rings, that contain 3 to 20,preferably 3 to 12, more preferably 3 to 9 carbon atoms. The cycloalkylradical may also be part of a bi- or polycyclic system, where, forexample, the cycloalkyl radical is fused to an aryl, heteroaryl orheterocyclyl radical as defined herein by any possible and desired ringmember(s). The bonding to the compounds of the general formula (I) canbe effected via any possible ring member of the cycloalkyl radical.Examples of suitable cycloalkyl radicals are cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclodecyl,cyclohexenyl, cyclopentenyl and cyclooctadienyl.

In a preferred embodiment of the invention, Cyc denotes cycloalkylhaving 3-7C atoms, in which 1-4H atoms may be replaced independently ofone another by Hal and/or which can be substituted by Ar. More preferredis C₃-C₆-cycloalkyl, which can be monosubstituted by Ar. Most preferredis C₃-C₆-cycloalkyl, i.e. cyclopropyl, cyclobutyl, cyclopentyl orcyclohexyl. Moreover, the definition of A shall also comprisecycloalkyls and it is to be applied mutatis mutandis to Cyc. It shall beunderstood that the respective denotation of Cyc is independently of oneanother in any radical of the invention.

The term “aryl” or “carboaryl” for the purposes of this invention refersto a mono- or polycyclic aromatic hydrocarbon systems having 3 to 14,preferably 5 to 10, more preferably 6 to 8 carbon atoms, which can beoptionally substituted. The term “aryl” also includes systems in whichthe aromatic cycle is part of a bi- or polycyclic saturated, partiallyunsaturated and/or aromatic system, such as where the aromatic cycle isfused to an aryl, cycloalkyl, heteroaryl or heterocyclyl group asdefined herein via any desired and possible ring member of the arylradical. The bonding to the compounds of the general formula (I) can beeffected via any possible ring member of the aryl radical. Examples ofsuitable aryl radicals are phenyl, biphenyl, naphthyl, 1-naphthyl,2-naphthyl and anthracenyl, but likewise in-danyl, indenyl or1,2,3,4-tetrahydronaphthyl. Preferred carboaryls of the invention areoptionally substituted phenyl, naphthyl and biphenyl, more preferablyoptionally substituted monocylic carboaryl having 6-8C atoms, mostpreferably optionally substituted phenyl.

In another embodiment of the invention, a carbocycle, including, but notlimited to, carboaryl, is defined as “Ar”. Examples of suitable Arradicals are phenyl, o-, m- or p-tolyl, o-, m- or p-ethylphenyl, o-, m-or p-propylphenyl, o-, m- or p-isopropylphenyl, o-, m- orp-tert.-butylphenyl, o-, m- or p-hydroxyphenyl, o-, m- orp-methoxyphenyl, o-, m- or p-ethoxyphenyl, o-, m- or p-fluorophenyl, o-,m- or p-bromophenyl, o-, m- or p-chlorophenyl, o-, m- orp-sulfonamido-phenyl, o-, m- or p-(N-methyl-sulfonamido)phenyl, o-, m-or p-(N,N-dimethyl-sulfonamido)phenyl, o-, m- orp-(N-ethyl-N-methyl-sulfonamido)phenyl, o-, m- orp-(N,N-diethyl-sulfonamido)-phenyl, particularly 2,3-, 2,4-, 2,5-, 2,6-,3,4- or 3,5-difluorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or3,5-dichlorophenyl, 2,3-, 2,4-, 2,5-, 2,6-, 3,4- or 3,5-dibromophenyl,2,3,4-, 2,3,5-, 2,3,6-, 2,4,6- or 3,4,5-trichlorophenyl,2,4,6-trimethoxyphenyl, 2-hydroxy-3,5-dichlorophenyl, p-iodophenyl,4-fluoro-3-chlorophenyl, 2-fluoro-4-bromophenyl,2,5-difluoro-4-bromophenyl, 3-bromo-6-methoxyphenyl,3-chloro-6-methoxyphenyl or 2,5-dimethyl-4-chlorophenyl.

Ar preferably denotes an unsaturated or aromatic mono- or bicycliccarbocycle having 3-12 C atoms, which can be substituted by at least onesubstituent selected from the group of Hal, A, (CY₂)_(n)—OY,(CY₂)_(n)—NYY, COOY, CONYY, NHCOY, SO₂Y, CN and phenoxy. In a morepreferred embodiment of the invention, Ar denotes an aromatic mono- orbicyclic carbocycle having 3-12C atoms, which can be substituted by atleast one substituent selected from the group of Hal, A, (CY₂)_(n)—OY,(CY₂)_(n)—NYY, SO₂Y, CN and phenoxy. In a most preferred embodiment ofthe invention, Ar denotes an aromatic monocyclic carbocycle having 4-10C atoms, which can be substituted by at least one substituent selectedfrom the group of Hal, A, (CY₂)_(n)—OY, (CY₂)_(n)—NYY, SO₂Y, CN andphenoxy. It is highly preferred that Ar denotes an aromatic monocycliccarbocycle having 6-8C atoms, which can be monosubstituted by Hal, A,OA, (CY₂)_(n)—OH, SO₂A or CN. In a particularly highly preferredembodiment of the invention, Ar denotes phenyl. It shall be understoodthat the respective denotation of Ar is independently of one another inany radical of the invention.

The term “heterocycle” or “heterocyclyl” for the purposes of thisinvention refers to a mono- or polycyclic system of 1-15 ring atoms,preferably 1-12 ring atoms, more preferably 3-9 ring atoms, comprisingcarbon atoms and 1, 2, 3, 4 or 5 heteroatoms, which are identical ordifferent, in particular nitrogen, oxygen and/or sulfur. The cyclicsystem may be saturated or mono- or poly-unsaturated, preferablyunsaturated. In the case of a cyclic system consisting of at least tworings the rings may be fused or spiro or otherwise connected. Suchheterocyclyl radicals can be linked via any ring member. The term“heterocyclyl” also includes systems in which the heterocycle is part ofa bi- or polycyclic saturated, partially unsaturated and/or aromaticsystem, such as where the heterocycle is fused to an aryl, cycloalkyl,heteroaryl or heterocyclyl group as defined herein via any desired andpossible ring member of the heterocyclyl radical. The bonding to thecompounds of the general formula (I) can be effected via any possiblering member of the heterocyclyl radical. Examples of suitableheterocyclyl radicals are pyrrolidinyl, thiapyrrolidinyl, piperidinyl,piperazinyl, oxapiperazinyl, oxapiperidinyl, oxadiazolyl,tetrahydrofuryl, imidazolidinyl, thiazolidinyl, tetrahydropyranyl,morpholinyl, tetrahydrothiophenyl, dihydropyranyl.

The terms “heteroaryl” for the purposes of this invention refers to a1-15, preferably 1-12, more preferably 3-9, most preferably 5-, 6- or7-membered mono- or polycyclic aromatic hydrocarbon radical whichcomprises at least 1, where appropriate also 2, 3, 4 or 5 heteroatoms,preferably nitrogen, oxygen and/or sulfur, where the heteroatoms areidentical or different. Preferably, the number of nitrogen atoms is 0,1, 2, 3 or 4, and that of the oxygen and sulfur atoms is independentlyfrom one another 0 or 1. The term “heteroaryl” also includes systems inwhich the aromatic cycle is part of a bi- or polycyclic saturated,partially unsaturated and/or aromatic system, such as where the aromaticcycle is fused to an aryl, cycloalkyl, heteroaryl or heterocyclyl groupas defined herein via any desired and possible ring member of theheteroaryl radical. The bonding to the compounds of the general formula(I) can be effected via any possible ring member of the heteroarylradical. Examples of suitable heteroaryl are pyrrolyl, thienyl, furyl,imidazolyl, thiazyl, isothiazyl, oxazyl, oxadiazyl, isoxazyl, pyrazyl,pyridyl, pyrimidyl, pyridazinyl, pyrazyl, indolyl, quinolyl,isoquinolinyl, imidazolyl, triazolyl, triazinyl, tetrazyl, phthalazinyl,indazolyl, indolizinyl, quinoxalinyl, quinazolinyl, pteridinyl,carbazolyl, phenazinyl, phenoxazinyl, phenothiazinyl and acridinyl.

It is preferred that heterocycle or heteroaryl in the realms of “Het”represents an unsaturated or aromatic mono-, bi- or tricyclicheterocycle having 1-12C atoms and 1-4 N atoms, which can be substitutedby at least one substituent selected from the group of Hal, A,(CY₂)_(n)—OY, (CY₂)_(n)—NYY, COOY, CONYY, NHCOY, SO₂Y, SO₂Ar, CN andthiophenyl. Suitable examples are pyrrolyl, imidazolyl, benzoimidazolyl,pyrazyl, triazolyl, benzotriazolyl, pyridyl and carbazolyl, which can beoptionally substituted. In a more preferred embodiment of the invention,Het denotes an unsaturated or aromatic mono-, bi- or tricyclicheterocycle having 2-12C atoms and 1-3 N atoms, which can be mono-, di-or trisubstituted by at least one substituent selected from the group ofHal, A, (CH₂)_(n)—OY, (CY₂)_(n)—NYY, SO₂Y, SO₂Ar, CN and thiophenyl. Itis most preferred that Het denotes an unsaturated or aromatic mono- orbicyclic heterocycle having 3-9C atoms and 1-3 N atoms, which can bemono-, di- or trisubstituted by at least one substituent selected fromthe group of A, SO₂Ar and thiophenyl. Highly preferred Het is anunsaturated or aromatic mono- or bicyclic heterocycle having 5-7C atomsand 1-3 N atoms. Benzotriazolyl is particularly preferred. It shall beunderstood that the respective denotation of Het is independently of oneanother in any radical of the invention.

The term “halogen”, “halogen atom”, “halogen substituent” or “Hal” forthe purposes of this invention refers to one or, where appropriate, aplurality of fluorine (F, fluoro), bromine (Br, bromo), chlorine (Cl,chloro) or iodine (I, iodo) atoms. The designations “dihalogen”,“trihalogen” and “perhalogen” refer respectively to two, three and foursubstituents, where each substituent can be selected independently fromthe group consisting of fluorine, chlorine, bromine and iodine. Halogenpreferably means a fluorine, chlorine or bromine atom. Fluorine andchlorine are more preferred, particularly when the halogens aresubstituted on an alkyl (haloalkyl) or alkoxy group (e.g. CF₃ and CF₃O).It is another preferred aspect that halogen denotes Cl, Br or I. Itshall be understood that the respective denotation of Hal isindependently of one another in any radical of the invention.

It is a preferred embodiment of the present invention that R¹, R², R³denote independently from one another H or A, more preferably H.

It is another preferred embodiment of the present invention that R⁴denotes Hal, H, OY, OCOOA, COOA, NYY, NAOA, N═N⁺═N⁻, CAr₃, (CH₂)_(n)—Ar,O—(CH₂)_(n)—Ar, NY—(CH₂)_(n)—Ar, NH—(CH₂)_(n)-Cyc, NH—(CH₂)_(n)-Het,

more preferably Hal, H, COOA, NYY, NAOA, (CH₂)_(n)—Ar, NH—(CH₂)_(n)-Cyc,NH—(CH₂)_(n)-Het,

and

most preferably Hal, NYY, (CH₂)_(n)—Ar or

It is another more preferred aspect of the invention that R⁴ denotesHal, H, COOY, SO₂Y, CN, CAr₃, (CH₂)_(m)—Ar,

most preferably Hal, H, COOY, CAr₃ or

highly preferably Hal or

and particularly highly preferably

It is another preferred embodiment of the present invention that R⁵denotes (CH₂)_(n)—Ar, (CH₂)_(n)-Cyc, (CH₂)_(n)-Het, (CH₂)_(n)—O—Ar,(CH₂)_(n)—CY(OH)—Ar or (CH₂)_(n)—NA-Ar; more preferably (CH₂)_(n)—Ar,(CH₂)_(n)-Cyc, (CH₂)_(n)-Het, (CH₂)_(n)—O—Ar or CY(OH)—Ar; and mostpreferably (CH₂)_(n)-Het, (CH₂)_(n)—O—Ar or CY(OH)—Ar.

It is another preferred embodiment of the present invention that Xdenotes CH₂, CO or CH(OH) with the proviso that CH₂ and/or CH(OH) areexcluded if R⁴ denotes H.

In an aspect of the invention, Y denotes H or A. It shall be understoodthat the respective denotation of Y is independently of one another inany radical of the invention.

It is a preferred embodiment of the m index according to the presentinvention to be 1 or 2, more preferably 2.

It is a preferred embodiment of the n index according to the presentinvention to be 0, 1, 2, 3, 4 or 5, more preferably 0, 1, 2, 3 or 4,most preferably 0, 1, 2 or 3. It shall be understood that the respectivedenotation of n is independently of one another in any radical of theinvention.

In another preferred aspect of the invention, one or more of thefollowing compounds are excluded from the scope of formula (I) or anysub-formula thereof:

Accordingly, the subject-matter of the invention relates to compounds offormula (I), in which at least one of the aforementioned radicals hasany meaning, particularly realize any preferred embodiment, as describedabove. Radicals, which are not explicitly specified in the context ofany embodiment of formula (I), sub-formulae thereof or other radicalsthereto, shall be construed to represent any respective denotationsaccording to formula (I) as disclosed hereunder for solving the problemof the invention. That means that the aforementioned radicals may adoptall designated meanings as each described in the prior or followingcourse of the present specification, irrespective of the context to befound, including, but not limited to, any preferred embodiments. Itshall be particularly understood that any embodiment of a certainradical can be combined with any embodiment of one or more otherradicals.

In another preferred embodiment of the present invention, derivatives ofsub-formulae (IA), (IB), (IC) are provided

wherein

-   R⁶ denotes Hal, Y, OY, OCOOY, COOY, NYY, N═N⁺═N⁻, CAr₃,    O—(CH₂)_(n)—Ar, NY—(CH₂)_(n)—Ar or

-   R⁷ denotes Y, OY, NYY, NYOY, (CH₂)_(n)—Ar, NY—(CH₂)_(n)—Ar,    NY—(CH₂)_(n)-Cyc, NY—(CH₂)_(n)-Het or

-   R⁸ denotes (CH₂)_(n)—Ar; and-   R¹, R², R³, R⁵, Y, A, Cyc, Ar, Het, Hal, m and n have the meaning as    defined above;-   and/or physiologically acceptable salts thereof.

It shall be understood that R⁶, R⁷ and R⁸ are different subsets of R⁴and can also be designated in relation to R⁴, e.g. R^(4-IA), R^(4-IB)and R^(4-IC).

It is another preferred embodiment of the present invention that R⁶denotes Hal, H, OY, OCOOA, COOY, NYY, N═N⁺═N⁻, CAr₃, O—(CH₂)_(n)—Ar,NH—(CH₂)_(n)—Ar or

more preferably Hal, H, COOY, CAr₃ or

most preferably Hal, COOA or

and highly preferably Hal or

It is another preferred embodiment of the present invention that R⁷denotes H, OY, NYY, NAOA, (CH₂)_(n)—Ar, NY—(CH₂)_(n)—Ar,NH—(CH₂)_(n)-Cyc, NH—(CH₂)_(n)-Het or

more preferably H, NYY, (CH₂)_(m)—Ar or

most preferably H, NAA, (CH₂)_(m)—Ar or

highly preferably H, (CH₂)_(m)—Ar or

and particularly highly preferably H.

In still another preferred embodiment of the present invention, acompound of sub-formula (IA), (IB) or (IC) is provided

wherein

-   R⁶ denotes Hal, H, COOY, CAr₃ or

more preferably Cl, Br, I, COOY, CAr₃ or

-   R⁷ denotes H, (CH₂)_(m)—Ar or

more preferably (CH₂)_(m)—Ar or

R⁸ denotes (CH₂)_(m)—Ar; and

-   R¹, R², R³, R⁵, Y, Ar, Het, Hal, m and n have the meaning as defined    above;-   and/or a physiologically acceptable salt thereof.

In another more preferred embodiment of the present invention,derivatives of sub-formulae (IA-1), (IA-2), (IB-1) are provided

wherein

-   R⁹ denotes Y, OY, (CH₂)_(n)—Ar, (CH₂)_(n)-Cyc or (CH₂)_(n)-Het; and-   R⁵, Y, A, Cyc, Ar, Het, Hal and n have the meaning as defined above;-   and/or physiologically acceptable salts thereof.

It is a preferred embodiment of the present invention that R⁹ denotes H,OA, (CH₂)_(n)—Ar, (CH₂)_(n)-Cyc or (CH₂)_(n)-Het; preferably NYY; andmore preferably NAA.

In still another more preferred embodiment of the present invention, acompound of sub-formula (IA-1) or (IA-2) is provided

wherein

-   R⁵, Y and Hal have the meaning as defined above;-   and/or a physiologically acceptable salt thereof.

It is a more preferred embodiment of Hal to be Cl, Br or I insub-formula (IA-1).

The prior teaching of the present specification concerning the compoundsof formula (I), including any radical definition and preferredembodiment thereof, is valid and applicable without restrictions to thecompounds according to sub-formulae (IA), (IA-1), (IA-2), (IB), (IB-1),(IC) and their salts if expedient.

Most preferred embodiments are those compounds of formulae (IA), (IA-1),(IA-2), (IB), (IB-1), (IC) as listed in Table 1.

TABLE 1 Compounds of formulae (IA), (IA-1), (IA-2), (IB), (IB-1), (IC).OGA enzyme inhibition assay: EXAMPLE 49. OGA cellular inhibition assay:EXAMPLE 50. OGA enzyme OGA cellular inhibition (IC50) inhibition (EC50)0 >1 μM 0 >1 μM + >0.5-1 μM + >0.5-1 μM ++ 0.1-0.5 μM ++ 0.1-0.5 μM No.Structure +++ <0.1 μM +++ <0.1 μM 1

+++ ++ 2

++ 0 3

++ +++ 4

+++ ++ 5

+++ ++ 6

+++ + 7

++ 0 8

0 9

0 10

++ + 11

++ 12

+++ +++ 13

0 14

+++ ++ 15

0 16

0 17

18

19

+ 0 20

21

22

23

0 24

25

26

27

28

0 30

++ 0 31

0 32

+++ +++ 33

0 34

35

36

0 37

38

39

40

41

42

0 43

+ 0 44

45

0 46

++ ++ 47

+++ 48

+ 49

+++ 50

+++ + 51

++ ++ 52

++ 53

++ ++ 54

0 55

0 56

++ 57

+++ 0 58

+++ + 59

0 60

0 61

++ 62

++ 63

++ 64

65

+++ 0 66

+++ 0 67

+++ +++ 68

+++ 0 69

++ ++ 70

+++ 0 71

++ 0 72

+++ ++ 73

+++ + 74

+++ 0 75

+++ 0 76

+++ 0 77

+++ ++ 78

+++ +++ 79

+++ ++ 80

+++ ++ 81

+++ 0 82

+++ 0 83

+ 84

++ 0 85

++ 86

+++ +++ 87

+++ + 88

+++ 0 89

+++ ++ 90

+++ 0 91

++ 0 92

+++ ++ 93

+++ 0 94

++ ++ 95

+++ 96

+++ 97

+++ 98

+++ 99

+++ 100

++ 101

++ 102

++ 103

104

105

0

Highly preferred embodiments are the compounds selected from the groupof

and/or physiologically acceptable salts thereof.

Particularly highly preferred embodiments are the compounds selectedfrom the group of

and/or physiologically acceptable salts thereof.

The compounds according to formula (I) and the starting materials forits preparation, respectively, are produced by methods known per se, asdescribed in the literature (for example in standard works, such asHouben-Weyl, Methoden der organischen Chemie [Methods of OrganicChemistry], Georg-Thieme-Verlag, Stuttgart), i.e. under reactionconditions that are known and suitable for said reactions.

Use can also be made of variants that are known per se, but are notmentioned in greater detail herein. If desired, the starting materialscan also be formed in-situ by leaving them in the un-isolated status inthe crude reaction mixture, but immediately converting them further intothe compound according to the invention. On the other hand, it ispossible to carry out the reaction stepwise.

The reactions are preferably performed under basic conditions. Suitablebases are metal oxides, e.g. aluminum oxide, alkaline metal hydroxide(potassium hydroxide, sodium hydroxide and lithium hydroxide, interalia), alkaline earth metal hydroxide (barium hydroxide and calciumhydroxide, inter alia), alkaline metal alcoholates (potassium ethanolateand sodium propanolate, inter alia), alkaline metal carbonates (e.g.,sodium bicarbonate) and several organic bases (e.g.,N,N-diisopropylethylamine, piperidine or diethanolamine, inter alia).

The reaction is generally carried out in an inert solvent. Suitableinert solvents are, for example, hydrocarbons, such as hexane, petroleumether, benzene, toluene or xylene; chlorinated hydrocarbons, such astrichloroethylene, 1,2-dichloroethane, carbon tetrachloride, chloroformor dichloromethane; alcohols, such as methanol, ethanol, isopropanol,n-propanol, n-butanol or tert-butanol; ethers, such as diethyl ether,diisopropyl ether, tetrahydrofuran (THF) or dioxane; glycol ethers, suchas ethylene glycol monomethyl or monoethyl ether, ethylene glycoldimethyl ether (diglyme); ketones, such as acetone or butanone; amides,such as acetamide, dimethylacetamide or dimethylformamide (DMF);nitriles, such as acetonitrile; sulfoxides, such as dimethyl sulfoxide(DMSO); carbon disulfide; carboxylic acids, such as formic acid, aceticacid or trifluoroacetic acid (TFA); nitro compounds, such asnitromethane or nitrobenzene; esters, such as ethyl acetate, or mixturesof the said solvents. Particular preference is given to DMF,dichloromethane, THF, H₂O, methanol, TFA, tert. butanol, tert.amylalcohol, triethylamine or dioxane.

Depending on the conditions used, the reaction time is between a fewminutes and 14 days, the reaction temperature is between about −30° C.and 140° C., normally between −10° C. and 130° C., preferably between30° C. and 125° C.

The present invention also relates to a process for manufacturingcompounds of formula (I) comprising the steps of:

-   (a) performing a one-pot or multiple-pot synthesis by reacting a    compound of formula (II), in the presence of a solvent,

-   -   wherein R¹ to R³ and X have the meaning as defined above,    -   to yield a compound of formula (I)

-   -   wherein R¹ to R⁴ and X have the meaning as defined above,        and optionally

-   (b) converting a base or an acid of the compound of formula (I) into    a salt thereof.

Compound nos. 1, 9 and 45 can be preferably used as intermediates, morepreferably as intermediates for the preparation of other compounds inthe meaning of the invention. Another preferred intermediate of theinvention is(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol.

The following reactions, including without limitations schemes,conditions and compounds, are particularly preferred and included in thescope of the present invention. It shall be understood that the radicalsR¹ to R³ are not limited to be H, but any member of the respectiveMarkush groups defining R¹ to R³ can be applied instead of H. The otherradicals have the meaning as defined above.

Compounds of sub-formula (IA-1) could be synthesized as depicted inScheme 1. The primary alcohol of(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol(Carbosynth catalog #MD08856) reacted selectively with a mixture oftriphenylphosphine and N-halosuccinimide (either NCS or NBS) in DMF togive the corresponding halogenated analog. The fluorinated analog wassynthesized by treating(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diolwith DAST in dichloromethane.

Compounds of sub-formula (IA-2) could be synthesized by the routedepicted in Scheme 2. In the first step, azidation of(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diolusing diphenylphosphoryl azide under Bose-Mitsunobu conditions affordedthe primary azide, selectively (compound no. 1). Subsequent treatment ofthe azide analog with various alkynes in the presence of coppercatalysts afforded the triazole cycloaddition products.

Compounds of sub-formula (IB-1) were synthesized according to the routeoutlined in Scheme 3. The amides were prepared in two steps: first,selective oxidation of the primary alcohol of(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diolto the carboxylic acid (compound no. 9; cf. e.g. EXAMPLE 48), thencoupling to various amines using 1-hydroxybenzotriazole and acarbodiimide.

Compounds of sub-formula (IC) were prepared using the route depicted inScheme 4. The C-6 carboxylic acid analog (compound no. 9; prepared asshown in Scheme 3) was converted to the corresponding Weinreb amide(compound no. 45) using N,O-dimethylhydroxylamine and propane phosphonicacid anhydride (T3P). Addition of Grignard reagents to the Weinreb amideproduced ketones that were subsequently reduced by sodium borohydride togenerate compounds with secondary alcohols at C-6.

The compounds of formula (I) are accessible via the routes above. Thestarting materials, including the compounds of formula (II), are usuallyknown to the skilled artisan, or they can be easily prepared by knownmethods. Accordingly, any compound of formula (II) can be purified,provided as intermediate product and used as starting material for thepreparation of compounds of formula (I).

The compounds of formula (I) can be modified, like hydrogenated ormetal-reduced, to remove the chlorine, or put into a substitutionreaction, and/or to be transformed with an acid or base into a salt,preferably with a strong acid. Numerous papers and methods are availableand useful for the one skilled in the art in respect for organicchemistry, chemical strategies and tactics, synthetic routes, protectionof intermediates, cleavage and purification procedure, isolation andcharacterization. General chemical modifications are known to the oneskilled in the art. Halogenation of aryls or hydroxy substitution byhalogens of acids, alcohols, phenols, and their tautomeric structurescan be preferably carried out by use of POCl₃, or SOCl₂, PCl₅, SO₂Cl₂.In some instances oxalyl chloride is also useful. Temperatures can varyfrom 0° C. to reflux depending on the task to halogenate a pyridonestructure or a carboxylic acid or a sulfonic acid. Time will also beadjusted from minutes to several hours or even over night. Similarly,alkylation, ether formation, ester formation, amide formation are knownto the one skilled in the art. Arylation with aryl boronic acids can beperformed in presence of a Pd catalyst, appropriate ligand and base,preferably a carbonate, phosphate, borate salt of sodium, potassium orcesium. Organic bases, like Et₃N, DIPEA or the more basic DBU can alsobe used. Solvents can vary too, from toluene, dioxane, THF, diglyme,monoglyme, alcohols, DMF, DMA, NMP, acetonitrile, in some cases evenwater, and others. Commonly used catalysts like Pd (PPh₃)₄, or Pd(OAc)₂,PdCl₂ type precursors of PdO catalysts have advanced to more complexones with more efficient ligands. In C—C arylations, instead of boronicacids and esters, aryl-trifluoroborate potassium salts (Suzuki-Miyauracoupling), organo silanes (Hiyama coupling), Grignard reagents (Kumada),organozinc compounds (Negishi coupling) and stannanes (Stifle coupling)may be useful. This experience can be transferred to N- andO-arylations. Numerous papers and methods are available and useful forthe one skilled in the art in respect of N-arylation and even ofelectron deficient anilines (Biscoe et al. JACS 130: 6686 (2008)), andwith aryl chlorides and anilines (Fors et al. JACS 130: 13552 (2008) aswell as for O-arylation by using Cu catalysis and Pd catalysis.

In the final step of the processes above, a salt of the compoundsaccording to formulae (I) to (II), preferably formula (I), is optionallyprovided. The said compounds according to the invention can be used intheir final non-salt form. On the other hand, the present invention alsoencompasses the use of these compounds in the form of theirpharmaceutically acceptable salts, which can be derived from variousorganic and inorganic acids and bases by procedures known in the art.Pharmaceutically acceptable salt forms of the compounds according to theinvention are for the most part prepared by conventional methods. If thecompound according to the invention contains a carboxyl group, one ofits suitable salts can be formed by the reaction of the compound with asuitable base to give the corresponding base-addition salt. Such basesare, for example, alkali metal hydroxides, including potassiumhydroxide, sodium hydroxide and lithium hydroxide; alkaline earth metalhydroxides, such as barium hydroxide and calcium hydroxide; alkali metalalkoxides, for example potassium ethoxide and sodium propoxide; andvarious organic bases, such as piperidine, diethanolamine andN-methylglutamine. The aluminum salts of the compounds according to theinvention are likewise included. In the case of certain compoundsaccording to the invention, acid-addition salts can be formed bytreating these compounds with pharmaceutically acceptable organic andinorganic acids, for example hydrogen halides, such as hydrogenchloride, hydrogen bromide or hydrogen iodide, other mineral acids andcorresponding salts thereof, such as sulfate, nitrate or phosphate andthe like, and alkyl- and monoarylsulfonates, such as ethanesulfonate,toluenesulfonate and benzenesulfonate, and other organic acids andcorresponding salts thereof, such as acetate, trifluoroacetate,tartrate, maleate, succinate, citrate, benzoate, salicylate, ascorbateand the like. Accordingly, pharmaceutically acceptable acid-additionsalts of the compounds according to the invention include the following:acetate, adipate, alginate, arginate, aspartate, benzoate,benzenesulfonate (besylate), bisulfate, bisulfite, bromide, butyrate,camphorate, camphorsulfonate, caprylate, chloride, chlorobenzoate,citrate, cyclopentanepropionate, digluconate, dihydrogenphosphate,dinitrobenzoate, dodecylsulfate, ethanesulfonate, fumarate, galacterate(from mucic acid), galacturonate, glucoheptanoate, gluconate, glutamate,glycerophosphate, hemisuccinate, hemisulfate, heptanoate, hexanoate,hippurate, hydrochloride, hydrobromide, hydroiodide,2-hydroxyethanesulfonate, iodide, isethionate, isobutyrate, lactate,lactobionate, malate, maleate, malonate, mandelate, metaphosphate,methanesulfonate, methylbenzoate, monohydrogenphosphate,2-naphthalenesulfonate, nicotinate, nitrate, oxalate, oleate, palmoate,pectinate, persulfate, phenylacetate, 3-phenylpropionate, phosphate,phosphonate, phthalate, but this does not represent a restriction.

With regard to that stated above, it can be seen that the expressions“pharmaceutically acceptable salt” and “physiologically acceptablesalt”, which are used interchangeable herein, in the present connectionare taken to mean an active ingredient which comprises a compoundaccording to the invention in the form of one of its salts, inparticular if this salt form imparts improved pharmacokinetic propertieson the active ingredient compared with the free form of the activeingredient or any other salt form of the active ingredient used earlier.The pharmaceutically acceptable salt form of the active ingredient canalso provide this active ingredient for the first time with a desiredpharmacokinetic property which it did not have earlier and can even havea positive influence on the pharmacodynamics of this active ingredientwith respect to its therapeutic efficacy in the body.

Object of the present invention is also the use of compounds accordingto formula (I) and/or physiologically acceptable salts thereof forinhibiting a glycosidase. The term “inhibition” denotes any reduction inglycosidase activity, which is based on the action of the specificinventive compounds capable to interact with the target glycosidase insuch a manner that makes recognition, binding and blocking possible. Thecompounds are characterized by such an appreciable affinity to at leastone glycoside hydrolase which ensures a reliable binding and preferablya complete blocking of glycosidase activity. More preferably, thesubstances are mono-specific in order to guarantee an exclusive anddirected recognition with the chosen single glycosidase target. In thecontext of the present invention, the term “recognition”-without beinglimited thereto—relates to any type of interaction between the specificcompounds and the target, particularly covalent or non-covalent bindingor association, such as a covalent bond, hydrophobic/hydrophilicinteractions, van der Waals forces, ion pairs, hydrogen bonds,ligand-receptor interactions, and the like. Such association may alsoencompass the presence of other molecules such as peptides, proteins ornucleotide sequences. The present receptor/ligand-interaction ispreferably characterized by high affinity, high selectivity and minimalor even lacking cross-reactivity to other target molecules to excludeunhealthy and harmful impacts to the treated subject.

In a preferred embodiment of the present invention, the glycosidasecomprises glycoside hydrolases, more preferably family 84 glycosidehydrolases, most preferablyO-glycoprotein-2-acetamido-2deoxy-β-D-glucopyranosidase (OGA), highlypreferably a mammalian O-GlcNAcase. It is particularly preferred thatthe compounds of formula (I) according to the invention selectively bindan O-GlcNAcase, e.g. thereby selectively inhibiting the cleavage of2-acetamido-2-deoxy-β-D-glucopyranoside (O-GlcNAc) while they do notsubstantially inhibit a lysosomal β-hexosaminidase.

The compounds according to the invention preferably exhibit anadvantageous biological activity, which is easily demonstrated in enzymeactivity assays as described herein or known from prior art. In suchin-vitro assays, the compounds preferably exhibit and cause aninhibitory effect. IC₅₀ is the concentration of a compound that produces50% of the maximal inhibition for that compound. The glycosidase targetis especially half inhibited by the compounds described herein if theconcentration of the compounds amounts to 1 μM or less, preferably 0.5μM or less, more preferably 0.2 μM or less, most preferably less than0.1 μM.

The advantageous biological activity of the compounds according to theinvention can also be demonstrated in cell-culture based assays, forexample assays as described in WO 2008/025170, which is incorporatedherein by reference. When testing compounds described herein in acellular assay, an increase in O-GlcNAcylation (due to the inhibition ofOGA) is measured. EC₅₀ is the effective concentration of a compound thatproduces 50% of the maximum possible response for that compound. Thecompounds of the invention exhibit EC₅₀ values in the range of 10 nM to25 μM. It is preferred that the compounds of the invention have anactivity, as expressed by an EC₅₀ standard, of 1 μM or less, preferably0.5 μM or less, more preferably 0.2 μM or less, most preferably lessthan 0.1 μM.

A preferred object of the present invention relates to a method forinhibiting a glycosidase, wherein a cell capable of expressing, orexpressing, the glycosidase is contacted with at least one compound offormula (I) according to the invention and/or physiologically acceptablesalts thereof under conditions such that the glycosidase is inhibited.The prior teaching of the present specification concerning the compoundsof formula (I), including any preferred embodiment thereof, is valid andapplicable without restrictions to the compounds according to formula(I) and their salts when used in the method for inhibiting aglycosidase.

As discussed herein, the glycosidase-signaling pathways are relevant forvarious diseases, preferably neurodegenerative diseases, diabetes,cancer and stress. Accordingly, the compounds according to the inventionare useful in the prophylaxis and/or treatment of diseases that aredependent on the said signaling pathways by interaction with one or moreof them. The present invention therefore relates to compounds accordingto the invention as inhibitors of the signaling pathways describedherein, preferably of the OGA-mediated signaling.

The method of the invention can be performed either in-vitro or in-vivo.The susceptibility of a particular cell to treatment with the compoundsaccording to the invention can be particularly determined by in-vitrotests, whether in the course of research or clinical application.Typically, a culture of the cell is combined with a compound accordingto the invention at various concentrations for a period of time which issufficient to allow the active agents to modulate glycosidase activity,usually between about one hour and one week. In-vitro treatment can becarried out using cultivated cells from any sample or cell line.

The host or patient can belong to any mammalian species, for example aprimate species, particularly humans; rodents, including mice, rats andhamsters; rabbits; horses, cows, dogs, cats, etc. Animal models are ofinterest for experimental investigations, providing a model fortreatment of human disease.

For identification of a signal transduction pathway and for detection ofinteractions between various signal transduction pathways, variousscientists have developed suitable models or model systems, for examplecell culture models and models of transgenic animals. For thedetermination of certain stages in the signal transduction cascade,interacting compounds can be utilized in order to modulate the signal.The compounds according to the invention can also be used as reagentsfor testing OGA-dependent signal transduction pathways in animals and/orcell culture models or in the clinical diseases mentioned in thisapplication.

The use according to the previous paragraphs of the specification may beeither performed in-vitro or in-vivo models. The inhibition can bemonitored by the techniques described in the course of the presentspecification. The in-vitro use is preferably applied to samples ofhumans suffering from neurodegenerative diseases, diabetes, cancer andstress. Testing of several specific compounds and/or derivatives thereofmakes the selection of that active ingredient possible that is bestsuited for the treatment of the human subject. The in-vivo dose rate ofthe chosen derivative is advantageously pre-adjusted to the glycosidasesusceptibility and/or severity of disease of the respective subject withregard to the in-vitro data. Therefore, the therapeutic efficacy isremarkably enhanced. Moreover, the subsequent teaching of the presentspecification concerning the use of the compounds according to formula(I) and its derivatives for the production of a medicament for theprophylactic or therapeutic treatment and/or monitoring is considered asvalid and applicable without restrictions to the use of the compound forthe inhibition of glycosidase activity, preferably OGA activity, ifexpedient.

The invention furthermore relates to a medicament comprising at leastone compound according to the invention and/or pharmaceutically usablederivatives, salts, solvates and stereoisomers thereof, includingmixtures thereof in all ratios. Preferably, the invention relates to amedicament comprising at least one compound according to the inventionand/or physiologically acceptable salts thereof.

A “medicament” in the meaning of the invention is any agent in the fieldof medicine, which comprises one or more compounds of formula (I) orpreparations thereof (e.g. a pharmaceutical composition orpharmaceutical formulation) and can be used in prophylaxis, therapy,follow-up or aftercare of patients who suffer from diseases, which areassociated with OGA activity, in such a way that a pathogenicmodification of their overall condition or of the condition ofparticular regions of the organism could establish at least temporarily.

Consequently, the invention also relates to a pharmaceutical compositioncomprising as active ingredient an effective amount of at least onecompound of formula (I) according to the invention and/orphysiologically acceptable salts thereof together with pharmaceuticallytolerable adjuvants and/or excipients.

In the meaning of the invention, an “adjuvant” denotes every substancethat enables, intensifies or modifies a specific response against theactive ingredient of the invention if administered simultaneously,contemporarily or sequentially. Known adjuvants for injection solutionsare, for example, aluminum compositions, such as aluminum hydroxide oraluminum phosphate, saponins, such as QS21, muramyldipeptide ormuramyltripeptide, proteins, such as gamma-interferon or TNF, M59,squalen or polyols.

Furthermore, the active ingredient may be administered alone or incombination with other treatments. A synergistic effect may be achievedby using more than one compound in the pharmaceutical composition, i.e.the compound of formula (I) is combined with at least another agent asactive ingredient, which is either another compound of formula (I) or acompound of different structural scaffold. The active ingredients can beused either simultaneously or sequentially. The present compounds aresuitable for combination with agents known to those of skill in the art(cf. e.g. WO 2008/025170, which is incorporated herein by reference) andare useful with the compounds of the present invention.

The invention also relates to a set (kit) consisting of separate packsof an effective amount of a compound according to the invention and/orpharmaceutically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient. The setcomprises suitable containers, such as boxes, individual bottles, bagsor ampoules. The set may, for example, comprise separate ampoules, eachcontaining an effective amount of a compound according to the inventionand/or pharmaceutically acceptable salts, derivatives, solvates andstereoisomers thereof, including mixtures thereof in all ratios, and aneffective amount of a further medicament active ingredient in dissolvedor lyophilized form.

Pharmaceutical formulations can be adapted for administration via anydesired suitable method, for example by oral (including buccal orsublingual), rectal, nasal, topical (including buccal, sublingual ortransdermal), vaginal or parenteral (including subcutaneous,intramuscular, intravenous or intradermal) methods. Such formulationscan be prepared using all processes known in the pharmaceutical art by,for example, combining the active ingredient with the excipient(s) oradjuvant(s).

The pharmaceutical composition of the invention is produced in a knownway using common solid or liquid carriers, diluents and/or additives andusual adjuvants for pharmaceutical engineering and with an appropriatedosage. The amount of excipient material that is combined with theactive ingredient to produce a single dosage form varies depending uponthe host treated and the particular mode of administration. Suitableexcipients include organic or inorganic substances that are suitable forthe different routes of administration, such as enteral (e.g. oral),parenteral or topical application, and which do not react with compoundsof formula (I) or salts thereof. Examples of suitable excipients arewater, vegetable oils, benzyl alcohols, alkylene glycols, polyethyleneglycols, glycerol triacetate, gelatin, carbohydrates, e.g. lactose orstarch, magnesium stearate, talc and petroleum jelly.

Pharmaceutical formulations adapted for oral administration can beadministered as separate units, such as, for example, capsules ortablets; powders or granules; solutions or suspensions in aqueous ornon-aqueous liquids; edible foams or foam foods; or oil-in-water liquidemulsions or water-in-oil liquid emulsions.

Pharmaceutical formulations adapted for parenteral administrationinclude aqueous and non-aqueous sterile injection solutions comprisingantioxidants, buffers, bacteriostatics and solutes, by means of whichthe formulation is rendered isotonic with the blood of the recipient tobe treated; and aqueous and non-aqueous sterile suspensions, which maycomprise suspension media and thickeners. The formulations can beadministered in single-dose or multi-dose containers, for example sealedampoules and vials, and stored in freeze-dried (lyophilized) state, sothat only the addition of the sterile carrier liquid, for example waterfor injection purposes, immediately before use is necessary. Injectionsolutions and suspensions prepared in accordance with the recipe can beprepared from sterile powders, granules and tablets.

It goes without saying that, in addition to the above particularlymentioned constituents, the formulations may also comprise other agentsusual in the art with respect to the particular type of formulation;thus, for example, formulations which are suitable for oraladministration may comprise flavors.

In a preferred embodiment of the present invention, the pharmaceuticalcomposition is adapted for oral administration. The preparations can besterilized and/or can comprise auxiliaries, such as carrier proteins(e.g. serum albumin), lubricants, preservatives, stabilizers, fillers,chelating agents, antioxidants, solvents, bonding agents, suspendingagents, wetting agents, emulsifiers, salts (for influencing the osmoticpressure), buffer substances, colorants, flavorings and one or morefurther active substances, for example one or more vitamins. Additivesare well known in the art, and they are used in a variety offormulations.

Accordingly, the invention also relates to a pharmaceutical compositioncomprising as active ingredient an effective amount of at least onecompound of formula (I) according to the invention and/orphysiologically acceptable salts thereof together with pharmaceuticallytolerable adjuvants for oral administration, optionally in combinationwith at least another active pharmaceutical ingredient. The priorteaching of the present specification concerning administration routeand combination product, respectively, is valid and applicable withoutrestrictions to the combination of both features if expedient.

The terms “effective amount” or “effective dose” or “dose” areinterchangeably used herein and denote an amount of the pharmaceuticalcompound having a prophylactically or therapeutically relevant effect ona disease or pathological conditions, i.e. which causes in a tissue,system, animal or human a biological or medical response which is soughtor desired, for example, by a researcher or physician. A “prophylacticeffect” reduces the likelihood of developing a disease or even preventsthe onset of a disease. A “therapeutically relevant effect” relieves tosome extent one or more symptoms of a disease or returns to normalityeither partially or completely one or more physiological or biochemicalparameters associated with or causative of the disease or pathologicalconditions. In addition, the expression “therapeutically effectiveamount” denotes an amount which, compared with a corresponding subjectwho has not received this amount, has the following consequence:improved treatment, healing, prevention or elimination of a disease,syndrome, condition, complaint, disorder or side-effects or also thereduction in the advance of a disease, complaint or disorder. Theexpression “therapeutically effective amount” also encompasses theamounts which are effective for increasing normal physiologicalfunction.

The respective dose or dosage range for administering the pharmaceuticalcomposition according to the invention is sufficiently high in order toachieve the desired prophylactic or therapeutic effect of reducingsymptoms of the aforementioned diseases. It will be understood that thespecific dose level, frequency and period of administration to anyparticular human will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general state of health, gender, diet, time and route of administration,rate of excretion, drug combination and the severity of the particulardisease to which the specific therapy is applied. Using well-known meansand methods, the exact dose can be determined by one of skill in the artas a matter of routine experimentation. The prior teaching of thepresent specification is valid and applicable without restrictions tothe pharmaceutical composition comprising the compounds of formula (I)if expedient.

Pharmaceutical formulations can be administered in the form of dosageunits which comprise a predetermined amount of active ingredient perdosage unit. The concentration of the prophylactically ortherapeutically active ingredient in the formulation may vary from about0.1 to 100 wt %. Preferably, the compound of formula (I) or thepharmaceutically acceptable salts thereof are administered in doses ofapproximately 0.5 to 1000 mg, more preferably between 1 and 700 mg, mostpreferably 5 and 100 mg per dose unit. Generally, such a dose range isappropriate for total daily incorporation. In other terms, the dailydose is preferably between approximately 0.02 and 100 mg/kg of bodyweight. The specific dose for each patient depends, however, on a widevariety of factors as already described in the present specification(e.g. depending on the condition treated, the method of administrationand the age, weight and condition of the patient). Preferred dosage unitformulations are those which comprise a daily dose or part-dose, asindicated above, or a corresponding fraction thereof of an activeingredient. Furthermore, pharmaceutical formulations of this type can beprepared using a process which is generally known in the pharmaceuticalart.

Although a therapeutically effective amount of a compound according tothe invention has to be ultimately determined by the treating doctor orvet by considering a number of factors (e.g. the age and weight of theanimal, the precise condition that requires treatment, severity ofcondition, the nature of the formulation and the method ofadministration), an effective amount of a compound according to theinvention for the treatment of neurodegenerative diseases, for exampleAlzheimer's disease, is generally in the range from 0.1 to 100 mg/kg ofbody weight of the recipient (mammal) per day and particularly typicallyin the range from 1 to 10 mg/kg of body weight per day. Thus, the actualamount per day for an adult mammal weighing 70 kg is usually between 70and 700 mg, where this amount can be administered as a single dose perday or usually in a series of part-doses (such as, for example, two,three, four, five or six) per day, so that the total daily dose is thesame. An effective amount of a salt or solvate or of a physiologicallyfunctional derivative thereof can be determined as the fraction of theeffective amount of the compound according to the invention per se. Itcan be assumed that similar doses are suitable for the treatment ofother conditions mentioned above.

The pharmaceutical composition of the invention can be employed asmedicament in human and veterinary medicine. According to the invention,the compounds of formula (I) and/or physiologically salts thereof aresuited for the prophylactic or therapeutic treatment and/or monitoringof diseases that are caused, mediated and/or propagated by OGA activity.It is particularly preferred that the diseases are neurodegenerativediseases, diabetes, cancer and stress, more preferably neurodegenerativediseases, most preferably tauopathies, highly preferably Alzheimer'sdisease. It shall be understood that the host of the compound isincluded in the present scope of protection according to the presentinvention.

The neurodegenerative disease or condition is more preferably selectedfrom the group of Alzheimer's disease, Amyotrophic lateral sclerosis(ALS), Amyotrophic lateral sclerosis with cognitive impairment (ALSci),Argyrophilic grain dementia, Bluit disease, Corticobasal degeneration(CBP), Dementia pugilistica, Diffuse neurofibrillary tangles withcalcification, Down's syndrome, Familial British dementia, FamilialDanish dementia, Frontotemporal dementia with parkinsonism linked tochromosome 17 (FTDP-17), Gerstmann-Straussler-Scheinker disease,Guadeloupean parkinsonism, Hallevorden-Spatz disease (neurodegenerationwith brain iron accumulation type 1), Multiple system atrophy, Myotonicdystrophy, Niemann-Pick disease (type C), Pallido-ponto-nigraldegeneration, Parkinsonism-dementia complex of Guam, Pick's disease(PiD), Postencephalitic parkinsonism (PEP), Prion diseases (includingCreutzfeldt-Jakob Disease (GJD), Variant Creutzfeldt-Jakob Disease(vCJD), Fatal Familial Insomnia, Kuru, Progressive supercorticalgliosis, Progressive supranuclear palsy (PSP), Richardson's syndrome,Subacute sclerosing panencephalitis, Tangle-only dementia, Huntington'sdisease and Parkinson's disease. Most preferred is Alzheimer's disease.

The invention also relates to the use of compounds according to formula(I) and/or physiologically acceptable salts thereof for the prophylacticor therapeutic treatment and/or monitoring of diseases that are caused,mediated and/or propagated by OGA activity. Furthermore, the inventionrelates to the use of compounds according to formula (I) and/orphysiologically acceptable salts thereof for the production of amedicament for the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byOGA activity. Compounds of formula (I) and/or a physiologicallyacceptable salt thereof can furthermore be employed as intermediate forthe preparation of further medicament active ingredients. The medicamentis preferably prepared in a non-chemical manner, e.g. by combining theactive ingredient with at least one solid, fluid and/or semi-fluidcarrier or excipient, and optionally in conjunction with a single ormore other active substances in an appropriate dosage form.

Another object of the present invention are compounds of formula (I)according to the invention and/or physiologically acceptable saltsthereof for use in the prophylactic or therapeutic treatment and/ormonitoring of diseases that are caused, mediated and/or propagated byOGA activity. Another preferred object of the invention concernscompounds of formula (I) according to the invention and/orphysiologically acceptable salts thereof for use in the prophylactic ortherapeutic treatment and/or monitoring of neurodegenerative diseases,diabetes, cancer and stress. The prior teaching of the presentspecification concerning the compounds of formula (I), including anypreferred embodiment thereof, is valid and applicable withoutrestrictions to the compounds according to formula (I) and their saltsfor use in the prophylactic or therapeutic treatment and/or monitoringof neurodegenerative diseases, diabetes, cancer and stress.

The compounds of formula (I) according to the invention can beadministered before or following an onset of disease once or severaltimes acting as therapy. The aforementioned compounds and medicalproducts of the inventive use are particularly used for the therapeutictreatment. A therapeutically relevant effect relieves to some extent oneor more symptoms of a disorder, or returns to normality, eitherpartially or completely, one or more physiological or biochemicalparameters associated with or causative of a disease or pathologicalcondition. Monitoring is considered as a kind of treatment provided thatthe compounds are administered in distinct intervals, e.g. in order tobooster the response and eradicate the pathogens and/or symptoms of thedisease completely. Either the identical compound or different compoundscan be applied. The medicament can also be used to reducing thelikelihood of developing a disorder or even prevent the initiation ofdisorders associated with OGA activity in advance or to treat thearising and continuing symptoms. The disorders as concerned by theinvention are preferably neurodegenerative diseases, diabetes, cancerand stress.

In the meaning of the invention, prophylactic treatment is advisable ifthe subject possesses any preconditions for the aforementionedphysiological or pathological conditions, such as a familialdisposition, a genetic defect, or a previously passed disease.

It is another object of the invention to provide a method for treatingdiseases that are caused, mediated and/or propagated by OGA activity,wherein an effective amount of at least one compound of formula (I)according to the invention and/or physiologically acceptable saltsthereof is administered to a mammal in need of such treatment. It isanother preferred object of the invention to provide a method fortreating neurodegenerative diseases, diabetes, cancer and stress,preferably a tauopathy, wherein an effective amount of at least onecompound of formula (I) according to the invention and/orphysiologically acceptable salts thereof is administered to a mammal inneed of such treatment. The preferred treatment is an oraladministration. The prior teaching of the invention and its embodimentsis valid and applicable without restrictions to the methods of treatmentif expedient.

In the scope of the present invention, compounds of formula (I) areprovided for the first time. The low molecular weight compounds of theinvention are strong and selective glycosidase inhibitors with improvedpassive permeability endowed by the more lipophilic moieties at C-6position. O-GlcNAcylation of nuclear and cytoplasmic proteins is one ofthe most common post-translational modifications in animals and plants.O-GlcNAc cycling modulates a number of cellular processes, and evidenceis mounting that dysregulation of O-GlcNAcylation plays a role in theetiology of several diseases, including Alzheimer's disease. O-GlcNActransferase (OGT) and O-GlcNAcase (OGA) are the two enzymes thatregulate O-GlcNAc cycling. Emerging data suggest that inhibitors thatblock OGA may help maintain healthy O-GlcNAc levels in Alzheimer'sdisease patients and thereby inhibit the formation of neurofibrillarytangles. Hence, the current invention comprises the use of compounds offormula (I) in the regulation, modulation and/or inhibition of theglycosidase signal cascade, which can be advantageously applied asresearch tool, for diagnosis and/or in treatment of any disorders thatare responsive to OGA signaling and inhibition.

The low molecular weight inhibitors can be applied either themselvesand/or in combination with physical measurements for diagnostics oftreatment effectiveness. Medicaments and pharmaceutical compositionscontaining said compounds and the use of said compounds to treatglycosidase-mediated conditions is a promising, novel approach for abroad spectrum of therapies causing a direct and immediate improvementin the state of health, whether in man and animal. The impact is ofspecial benefit to efficiently combat Alzheimer's disease, either aloneor in combination with other neurodegenerative treatments.

Due to the surprisingly appreciable inhibitory activity on OGA, alongwith passive permeability, the compounds of the invention can beadvantageously administered at lower doses compared to other less potentor selective inhibitors of prior art while still achieving equivalent oreven superior desired biological effects. In addition, such a dosereduction advantageously leads to less or even no medicinal adverseeffects.

The compounds of formula (I), their salts, isomers, tautomers,enantiomeric forms, diastereomers, racemates, derivatives, prodrugsand/or metabolites are characterized by a high specificity andstability, low manufacturing costs and convenient handling. Thesefeatures form the basis for a reproducible action, wherein the lack ofcross-reactivity is included, and for a reliable and safe interactionwith the target structure.

All the references cited herein are incorporated by reference in thedisclosure of the invention hereby.

It is to be understood that this invention is not limited to theparticular compounds, pharmaceutical compositions, uses and methodsdescribed herein, as such matter can, of course, vary. It is also to beunderstood that the terminology used herein is for the purpose ofdescribing particular embodiments only and is not intended to limit thescope of the present invention, which is only defined by the appendedclaims. As used herein, including the appended claims, singular forms ofwords such as “a,” “an,” and “the” include their corresponding pluralreferents unless the context clearly dictates otherwise. Thus, e.g.,reference to “a compound” includes a single or several differentcompounds, and reference to “a method” includes reference to equivalentsteps and methods known to a person of ordinary skill in the art, and soforth. Unless otherwise defined, all technical and scientific terms usedherein have the same meaning as commonly understood by a person ofordinary skill in the art to which this invention belongs.

The techniques that are essential according to the invention aredescribed in detail in the specification. Other techniques which are notdescribed in detail correspond to known standard methods that are wellknown to a person skilled in the art, or the techniques are described inmore detail in cited references, patent applications or standardliterature. Although methods and materials similar or equivalent tothose described herein can be used in the practice or testing of thepresent invention, suitable examples are described below. The followingexamples are provided by way of illustration and not by way oflimitation. Within the examples, standard reagents and buffers that arefree from contaminating activities (whenever practical) are used. Theexamples are particularly to be construed such that they are not limitedto the explicitly demonstrated combinations of features, but theexemplified features may be unrestrictedly combined again if thetechnical problem of the invention is solved. Similarly, the features ofany claim can be combined with the features of one or more other claims.

In the following examples, “conventional workup” means: water was addedif necessary, the pH was adjusted, if necessary, to a value of between 2and 10, depending on the constitution of the end product, the mixturewas extracted with ethyl acetate or dichloromethane, the phases wereseparated, the organic phase was dried over sodium sulfate andevaporated, and the product was purified by chromatography on silica geland/or by crystallization. R_(f) values were determined on silica gel.The eluent was ethyl acetate/methanol 9:1.

LCMS and HPLC analysis as well as ¹H NMR were performed as follows:

LCMS-Analysis:

Method A: A—0.1% TFA in H₂O, B—0.1% TFA in ACN: Flow—0.8 mL/min.

Gradient: 5-95% B in 3.5 min; Wavelength: 254 nm; Mass Scan: 100-900 Da.

Column: XBridge C8 (50×4.6 mm, 5 μm).

Method B: A—10 mM NH₄HCO₃ in H₂O, B—ACN; Flow—1.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm).

HPLC: —Analysis:

Method A: A—0.1% TFA in H₂O, B—0.1% TFA in ACN: Flow—2.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm).

Method B: A—10 mM NH₄HCO₃ in H₂O, B—ACN; Flow—1.0 mL/min.

Column: XBridge C8 (50×4.6 mm, 3.5 μm).

RT: retention time

¹H NMR was recorded on a Jeol 400 MHz or a Varian 500 MHz spectrometer,using residual signal of deuterated solvent as internal reference.Chemical shifts (δ) are reported in ppm relative to the residual solventsignal (δ=2.49 ppm for ¹H NMR in DMSO-d6). ¹H NMR data are reported asfollows: chemical shift (multiplicity, coupling constants, and number ofhydrogens). Multiplicity is abbreviated as follows: s (singlet), d(doublet), t (triplet), q (quartet), m (multiplet), br (broad).

EXAMPLE 13aR,5R,6S,7R,7aR)-2-(ethylamino)-5-[(4-pyridin-2-yl-1H-1,2,3-triazol-1-yl)methyl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 7

In a 5 mL seal vial equipped with a stir bar, a septum was added(3aR,5R,6S,7R,7aR)-5-(azidomethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(40.00 mg; 0.15 mmol; 1.00 eq.), copper Not supported by ACD (65.10 mg;1.02 mmol; 7.00 eq.) and copper(2+) sulfate pentahydrate (7.31 mg; 0.03mmol; 0.20 eq.). The vial was evacuated and filled with N₂. Thisprocedure was repeated for twice before ethanol (0.40 ml)/water (0.60ml)/2-methylpropan-2-ol (1.00 ml) and 2-ethynylpyridine (0.03 ml; 0.29mmol; 2.00 eq.) was added into the mixture. The mixture was stirred atroom temperature for overnight before 3 mL H₂O was added into themixture and dried via lyophilization. The mixture was purified withYamazen C1 acidic condition affording 14.4 mg (20.1%) of the titlecompound as a white solid (HPLC 99%, retention time=1.73 min) oncelyophilized.

¹H NMR (DMSO-d6) δ 8.60 (m, 1H), 8.44 (s, 1H), 8.03 (d, J=8.0 Hz, 1H),7.90 (ddd, J=7.6, 7.6, 1.6 Hz, 1H), 7.35 (m, 1H), 6.21 (d, J=1.6 Hz,1H), 5.35 (bs, 1H), 5.27 (bs, 1H), 4.76 (dd, J=14.4, 2.4 Hz, 1H), 4.54(dd, J=14.4, 8.4 Hz, 1H), 4.01 (dd, J=1.6, 1.6 Hz, 1H), 3.86 (dt, J=4.8,4.8 Hz, 1H), 3.75 (m, 1H), 3.39 (m, 1H), 3.14 (q, J=6.8 Hz, 2H), 1.05(t, J=7.2 Hz, 3H);

MS (m/z): 377 [M+H]⁺.

EXAMPLE 23aR,5R,6S,7R,7aR)-2-(ethylamino)-5-[(4-phenyl-1H-1,2,3-triazol-1-yl)methyl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 2

The title compound was prepared with the above method usingethynylbenzene (0.01 ml; 0.11 mmol; 1.50 eq.). The mixture was purifiedwith Yamazen Channel 2 (neutral condition) to afford 8.4 mg (31%) of thetitle compound as a white solid once lyophilized.

¹H NMR (DMSO-d6) δ 8.30 (s, 1H), 7.75 (d, J=7.2 Hz, 2H), 7.48 (dd,J=7.2, 7.2 Hz, 2H), 7.41 (dd, J=7.6, 7.6 Hz, 1H), 6.21 (d, J=6.0 Hz,1H), 4.63 (dd, J=14.8, 8.0 Hz, 1H), 4.17 (dd, J=6.0, 6.0 Hz, 1H), 4.05(dd, J=4.8, 4.8 Hz, 1H), 3.92 (dd, J=6.8, 6.8 Hz, 1H), 3.54 (dd, J=9.6,4.8 Hz, 1H), 3.20 (m, 2H), 1.09 (t, J=8.8 Hz, 3H);

MS (m/z): 376 [M+H]⁺.

EXAMPLE 33aR,5R,6S,7R,7aR)-5-[(4-benzyl-1H-1,2,3-triazol-1-yl)methyl]-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 14

The title compound was prepared with the above method usingprop-2-yn-1-ylbenzene (0.03 ml; 0.27 mmol; 2.00 eq.). The mixture waspurified with was purified via Waters pre-HPLC (flow rate 40 mL/min,desired product efflux at H₂O/ACN=64/36) to afford 26.3 mg (39%) of thetitle compound as a white solid once lyophilized.

¹H NMR (D₂O) δ 7.82 (s, 1H), 7.25-7.40 (m, 5H), 6.47 (d, J=6.8 Hz, 1H),4.63 (dd, J=12.4, 4.4 Hz, 1H), 4.20 (dd, J=6.8, 6.8 Hz, 1H), 4.06 (s,2H), 4.01 (m, 2H), 3.47 (dd, J=9.6, 6.8 Hz, 1H), 3.37 (qd, J=7.2, 2.4Hz, 2H), 1.21 (t, J=6.8 Hz, 3H);

MS (m/z): 390 [M+H]⁺.

EXAMPLE 43aR,5R,6S,7R,7aR)-2-(ethylamino)-5-{[4-(2-phenylethyl)-1H-1,2,3-triazol-1-yl]methyl}-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 6

The title compound was prepared with the above method usingbut-3-yn-1-ylbenzene (0.03 ml; 0.22 mmol; 1.50 eq.). The mixture waspurified with Yamazen Channel 1 (neutral condition, 35 g Interchim C18column, flow rate 30 mL/min, desired product showed up at H₂O/ACN=60/40)to give 35.3 mg (47%) of the title compound as a white solid oncelyophilized.

¹H NMR (D₂O) δ 7.42 (s, 1H), 7.01-7.22 (m, 4H), 6.05 (d, J=4.8 Hz, 1H),4.53 (m, 1H), 4.36 (dd, J=12.4, 12.0 Hz, 1H), 4.01 (dd, J=4.8, 4.8 Hz,1H), 3.91 (dd, J=4.0, 4.0 Hz, 1H), 3.69 (m, 1H), 3.32 (dd, J=6.8, 3.6Hz, 1H), 3.09 (m, 2H), 2.90 (m, 2H), 2.85 (m, 2H), 1.00 (t, J=5.6 Hz,3H);

MS (m/z): 404 [M+H]⁺.

EXAMPLE 53aR,5R,6S,7R,7aR)-2-(ethylamino)-5-{[4-(3-phenylpropyl)-1H-1,2,3-triazol-1-yl]methyl}-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 30

The title compound was prepared with the above method usingpent-4-yn-1-ylbenzene (120.2 μl; 0.787 mmol; 4.00 eq.). The mixture waspurified with Waters pre-HPLC (flow rate 60 mL/min, desired productefflux at H₂O/ACN=53/47) to give 11.1 mg (11%) of the title compound asa white solid once lyophilized.

¹H NMR (MeOH-d4) δ 7.73 (s, 1H), 7.20-7.28 (m, 2H), 7.10-7.20 (m, 3H),6.50 (d, J=6.8 Hz, 1H), 4.80 (dd, J=14.8, 7.2 Hz, 1H), 4.61 (dd, J=4.8,4.8 Hz, 1H), 4.19 (dd, J=6.4 Hz, 1H), 3.99 (m, 1H), 3.94 (dd, J=4.0, 4.0Hz, 1H), 3.41 (m, 3H), 2.70 (dd, J=7.6, 7.6 Hz, 2H), 2.64 (dd, J=7.6,7.6 Hz, 2H), 1.97 (m, 2H), 1.26 (t, J=7.2 Hz, 3H);

MS (m/z): 417 [M+H]⁺.

EXAMPLE 6 Methyl1-{[(3aR,5R,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-5-yl]methyl}-1H-1,2,3-triazole-4-carboxylate(compound no. 10)

The title compound was prepared with the above method using methylpropiolate (0.03 ml; 0.35 mmol; 2.00 eq.). The mixture was purified withWaters pre-HPLC to give 12.1 mg (15%) of the title compound as a whitesolid once lyophilized.

¹H NMR (D2O) δ 8.56 (s, 1H), 6.53 (d, J=6.8 Hz, 1H), 4.90 (m, 1H), 4.22(dd, J=6.8, 6.8 Hz, 1H), 4.12 (m, 1H), 4.02 (dd, J=6.8, 6.8 Hz, 1H),3.93 (s, 3H), 3.46 (dd, J=9.2, 6.4 Hz, 1H), 3.38 (m, 2H), 1.21 (t, J=7.2Hz, 3H);

MS (m/z): 358 [M+H]⁺.

EXAMPLE 73aR,5R,6S,7R,7aR)-2-(ethylamino)-5-{[4-(methoxymethyl)-1H-1,2,3-triazol-1-yl]methyl}-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound II

The title compound was prepared with the above method using3-methoxyprop-1-yne (0.03 ml; 0.35 mmol; 2.00 eq.). The mixture waspurified with Waters pre-HPLC to give 8.2 mg (10%) of the title compoundas a white solid once lyophilized.

¹H NMR (D2O) δ 8.16 (bs, 1H), 6.49 (d, J=6.8 Hz, 1H), 4.55 (bs, 2H),4.19 (dd, J=6.8, 6.8 Hz, 1H), 4.05 (m, 1H), 3.99 (dd, J=6.8, 6.8 Hz,1H), 3.26-3.45 (m, 6H), 2.68 (s, 1H), 1.19 (t, J=7.2 Hz, 3H);

MS (m/z): 344 [M+H]⁺.

EXAMPLE 8(3aR,5R,6S,7R,7aR)-5-{[4-(1H-1,2,3-benzotriazol-1-ylmethyl)-1H-1,2,3-triazol-1-yl]methyl}-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 57)

The title compound was prepared with the above method using1-prop-2-yn-1-yl-1H-1,2,3-benzotriazole (100.66 μl; 0.66 mmol; 3.00eq.). The mixture was purified with Waters pre-HPLC to give 32.6 mg(27%) of the title compound as a light blue foam once lyophilized.

¹H NMR (MeOH-d4) δ 7.81-8.08 (m, 3H), 7.47 (dd, J=5.6, 5.6 Hz, 1H), 7.35(bs, 1H), 6.41 (d, J=5.2 Hz, 1H), 5.95 (s, 2H), 4.55 (dd, J=11.6, 5.6Hz, 1H), 4.07 (dd, J=5.2, 5.2 Hz, 1H), 3.88 (dd, J=6.8, 6.8 Hz, 1H),3.81 (dd, J=4.8, 4.8 Hz, 1H), 3.33 (m, 3H), 1.16 (dd, J=6.0, 6.0 Hz,1H);

MS (m/z): 431 [M+H]⁺.

EXAMPLE 93aR,5R,6S,7R,7aR)-2-(ethylamino)-5-{[4-(phenoxymethyl)-1H-1,2,3-triazol-1-yl]methyl}-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 58

The title compound was prepared with the above method using(prop-2-yn-1-yloxy)benzene (112.81 μl; 0.88 mmol; 3.00 eq.). The mixturewas purified with Waters pre-HPLC to give 33.1 mg (28%) of the titlecompound as a white foam once lyophilized.

¹H NMR (MeOH-d4) δ 7.95 (s, 1H), 7.18 (dd, J=6.0, 6.0 Hz, 2H), 6.90 (d,J=7.2 Hz, 2H), 6.86 (dd, J=6.4, 6.4 Hz, 1H), 6.44 (d, J=5.2 Hz, 1H),5.06 (s, 2H), 4.59 (dd, J=11.6, 6.0 Hz, 1H), 4.08 (dd, J=5.2, 5.2 Hz,1H), 3.93 (dd, J=7.2, 7.2 Hz, 1H), 3.83 (dd, J=5.2, 5.2 Hz, 1H), 3.31(m, 3H), 1.17 (t, J=6.0 Hz, 3H);

MS (m/z): 406 [M+H]⁺.

EXAMPLE 103aR,5R,6S,7R,7aR)-5-(azidomethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 50

The title compound was prepared with the above method usingprop-2-yn-1-ylcyclohexane (127.16 μl; 0.88 mmol; 3.00 eq.). The mixturewas purified with Waters pre-HPLC (product efflux at H₂O/ACN=53/47) togive 45.2 mg (39.0%) of the title compound as a white foam oncelyophilized.

¹H NMR (MeOH-d4) δ 7.60 (s, 1H), 6.47 (d, J=5.2 Hz, 1H), 4.71 (dd,J=12.0, 2.0 Hz, 1H), 4.50 (dd, J=11.6, 6.0 Hz, 1H), 4.11 (dd, J=5.2, 5.2Hz, 1H), 3.89 (ddd, J=2.0, 5.6, 5.6 Hz, 1H), 3.84 (dd, J=5.2, 5.2 Hz,1H), 3.35 (m, 1H), 3.30 (m, 2H), 2.47 (d, J=5.6 Hz, 2H), 1.44-1.63 (m,7H), 1.05-1.22 (m, 5H), 0.88 (m, 2H);

MS (m/z): 396 [M+H]⁺.

EXAMPLE 113aR,5S,6S,7R,7aR)-5-(chloromethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 32

In a 5 mL seal vial equipped with a stir bar was added(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(30.00 mg; 0.12 mmol; 1.00 eq.) and 1-chloropyrrolidine-2,5-dione (24.20mg; 0.18 mmol; 1.50 eq.) in N,N-dimethylformamide (1.00 ml) followed bytriphenylphosphine (63.38 mg; 0.24 mmol; 2.00 eq.). After the clearsolution was stirred at 50° C. for 2 h, color became wine red. Thereaction was stirred for overnight before it is concentrated anddissolved in 2 mL MeOH. Yamazen HPLC Channel1 (acidic condition, 220 nm,55 g Interchim column, product efflux at H₂O/ACN=75/25) was used toisolate 5.4 mg (12%) of the title compound as a white solid oncelyophilized.

¹H NMR (D2O) δ 6.60 (d, J=6.8 Hz, 1H), 4.27 (dd, J=6.8 Hz, 1H), 4.02(dd, J=7.2 Hz, 2H), 3.90 (m, 2H), 3.75 (dd, J=7.6 Hz, 1H), 3.41 (m, 2H),1.25 (t, J=7.6 Hz, 3H);

MS (m/z): 267 [M+H]⁺.

EXAMPLE 123aR,5S,6S,7R,7aR)-5-(bromomethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 5

The title compound was prepared with the above method using1-bromopyrrolidine-2,5-dione (69.89 mg; 0.39 mmol; 1.50 eq.). Themixture was purified by Yamazen C1 (acidic condition, 55 g C18 columnfrom Interchim 30 μm, flow rate 20 mL/min, desired product efflux at(H₂O/ACN=65/35) to isolate 23.3 mg (27%) of the title compound as awhite solid once lyophilized.

¹H NMR (D2O) δ 6.56 (d, J=6.8 Hz, 1H), 4.24 (dd, J=6.8 Hz, 1H), 3.99(dd, J=7.2 Hz, 1H), 3.92 (m, 1H), 3.74 (m, 1H), 3.70 (m, 2H), 3.38 (m,2H), 1.21 (t, J=7.6 Hz, 3H);

MS (m/z): 312 [M+H]⁺.

EXAMPLE 133aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carbaldehyde(compound no. 47

In a dry sealed vial was added(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-N-methoxy-N-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxamide(70.00 mg; 0.23 mmol; 1.00 eq.) in toluene (1.00 ml) and tetrahydrofuran(1.00 ml). The clear solution was cooled to −78° C. beforehydrido(diisobutyl)aluminum (962.81 μl; 1.00 M; 0.96 mmol; 4.20 eq.) wasadded slowly. The obtained solution was stirred at −78° C. for 3 hbefore the reaction was quenched by addition of 1 mL H₂O at −78° C. Theobtained mixture was stirred at this temperature for 5 min before it iswarmed up to room temperature. The mixture was filtered and the obtainedfiltrated was dried with lyophilize to afford the title compound aswhite solid.

¹H NMR (D₂O) δ 6.19 (d, J=6.0 Hz, 1H), 5.02 (dd, J=3.0 Hz, 1H), 4.08(dd, J=6.0 Hz, 1H), 3.92 (dd, J=4.5 Hz, 1H), 3.63 (dd, J=9.5, 5.0 Hz,1H), 3.40 (m, 1H), 3.11 (m, 2H), 1.02 (t, J=6.5 Hz, 3H);

MS (m/z): 247 [M+H]⁺; 265 [M+H+18]⁺.

EXAMPLE 143aR,5S,6S,7R,7aR)-2-[ethyl(methyl)amino]-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxylicacid (compound no. 36

In a 5 mL sure seal vial was added(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxylicacid (53.00 mg; 0.20 mmol; 1.00 eq.) in N,N-dimethylformamide (2.00 ml)followed by dipotassium carbonate (55.85 mg; 0.40 mmol; 2.00 eq.) andiodomethane (29.69 μl; 0.40 mmol; 2.00 eq.). The mixture was stirred atroom temperature for overnight before it was concentrated, purified byYamazen C1 (40 g column, 220 nm) and dried with lyophilize to afford 7.3mg (9.3%) monomethylated compound as white solid and two sets of peakswere found on NMR, ratio=3:1.

¹H NMR (D2O) of major peak δ 6.41 (d, J=7.0 Hz, 1H), 5.48 (d, J=7.0 Hz,1H), 4.30 (dd, J=6.0 Hz, 1H), 4.223 (dd, J=6.5 Hz, 1H), 4.08 (dd, J=6.5Hz, 1H), 3.80 (s, 3H), 3.41 (m, 2H), 1.24 (t, J=9.0 Hz, 3H)

MS (m/z): 277 [M+H]⁺.

EXAMPLE 16Methyl-(3aR,5S,6S,7R,7aR)-2-[(tert-butoxycarbonyl)(ethyl)amino]-6,7-di-hydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxylate(compound no. 103)

In a dry sure-seal vial was added(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxylicacid (600.00 mg; 2.17 mmol; 1.00 eq.), di-tert-butyl dicarbonate (568.69mg; 2.61 mmol; 1.20 eq.) and tBuOH (4.00 ml). The clear solution wasstirred at room temperature overnight. The solution was concentrated,diluted with DCM, purified with 40 g Interchim HP column (30 μm). Onlyone peak was detected, efflux from EtOAc/Hex=55:45, ends atEtOAc/Hex=65:35. The collected solution was concentrated and lyophilizedto afford 535.0 mg (66%) of the title compound as a mixture of apartially sticky white foam and white solid.

¹H NMR (DMSO) δ 6.01 (d, J=5.0 Hz, 1H), 4.20 (dd, J=4.5 Hz, 1H), 4.79(dd, J=5.5 Hz, 1H), 4.00 (dd, J=5.5 Hz, 1H), 3.91-3.97 (m, 3H), 3.75 (s,3H), 1.54 (s, 9H), 1.18 (t, J=7.0 Hz, 3H);

MS (m/z): 377 [M+H]⁺.

EXAMPLE 173aR,5R,6S,7R,7aR)-5-(azidomethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 1

In a 2.5 mL seal vial equipped with a stir bar was added(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(150.00 mg; 0.60 mmol; 1.00 eq.) in tetrahydrofuran (2.00 ml) followedby triphenylphosphine (316.90 mg; 1.21 mmol; 2.00 eq.), isopropyl(Z)-(isopropoxyacetyl)diazenecarboxylate (0.25 ml; 1.21 mmol; 2.00 eq.).Diphenyl azidophosphate (0.26 ml; 1.21 mmol; 2.00 eq.) was then addeddropwise in 15 min. During the addition, the former obtainedgreen-yellow clear solution slowly turned to turbid and finally becameclear again. The mixture was stirred at room temperature for 48 h. Themixture was purified via Yamazen channel 2 and lyophilized to provide134.6 mg (81%) of the title compound as white solid.

¹H NMR (D2O) δ 6.27 (d, J=6.4 Hz, 1H), 4.18 (dd, J=6.4 Hz, 1H), 4.02(dd, J=4.8 Hz, 1H), 3.71 (m, 1H), 3.56-3.64 (m, 2H), 3.49 (dd, J=13.6,6.8 Hz, 1H), 3.21 (m, 2H), 1.11 (t, J=7.2 Hz, 3H);

MS (m/z): 289 [M+H]⁺.

EXAMPLE 182E)-N-[(3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-2-yl]but-2-enamide(compound no. 19

To a 10 mL reaction vial was added(3aR,5R,6S,7R,7aR)-5-[(acetyloxy)methyl]-2-[(2E)-but-2-enoylamino]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diyldiacetate(40.00 mg; 0.10 mmol; 1.00 eq.) in methanol (2.00 ml) followed by sodiummethanolate (0.00 ml;

0.01 mmol; 0.10 eq.). The obtained clear solution was stirred at roomtemperature for 1 h.

LCMS showed a strong peak of SM plus desired product and byproduct(m/z=331). After 5 h, LMCS only showed the product's peak. The solutionwas diluted with 10 mL MeOH before it was transferred into a 50 mLround-bottom flask. Half spoon resin (Dowex 50WX8) was added. Themixture was gently stirred for 10 sec before it was filtered. 30 mL MeOHwas used to rinsed the cake. The obtained solution was concentrated andlyophilized to afford 90.6% of the title compound as a white solid.

¹H NMR (MeOH) δ 6.22 (d, J=6.8 Hz, 1H), 5.98 (s, 1H), 5.69 (d, J=0.8 Hz,1H), 4.15 (dd, J=6.0 Hz, 1H), 4.06 (dd, J=6.0 Hz, 1H), 3.80-3.82 (m,1H), 3.70 (dd, J=12.4, 6.0 Hz, 1H), 3.58 (m, 2H), 1.93 (s, 3H);

MS (m/z): 274 [M+H]⁺.

EXAMPLE 193aR,5R,6S,7R,7aR)-5-(aminomethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 61

To(3aR,5R,6S,7R,7aR)-5-(azidomethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(40.00 mg; 0.15 mmol; 1.00 eq.) in methanol (1.00 ml) was added aceticacid (10.00 μl. The mixture was passed through the H-cube instrument(20% Pd(OH)₂) cartridge, full H₂, at 40° C., continuously for 1 h.Mixture was concentrated. The desired material was isolated by flashcolumn chromatography (KPNH column, 0 to 80% MeOH/DCM) to afford(3aR,5R,6S,7R,7aR)-5-(aminomethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol,(10.9 mg, 30%) as a white solid (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 6.29 (d, J=6.4, 1H), 4.06 (t, J=6.1, 1H), 3.93(t, J=5.4, 1H), 3.55 (ddd, J=9.2, 7.9, 3.0, 1H), 3.39 (dd, J=9.2, 5.1,1H), 3.30-3.20 (m, 2H), 2.97 (dd, J=13.4, 3.0, 1H), 2.73 (dd, J=13.5,7.6, 1H), 1.17 (t, J=7.2, 3H);

MS (m/z): 247; 248 [M+H]+

EXAMPLE 20tert-butyl[(3aR,5R,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-5-yl]methylcarbonate (compound no. 3)

To(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(50.00 mg; 0.20 mmol; 1.00 eq.) in THF (2.00 ml) and DMF (0.05 ml) undernitrogen was added di-tert-butyl dicarbonate (52.74 mg; 0.24 mmol; 1.20eq.), 4-(dimethylamino)pyridine (4.92 mg; 0.04 mmol; 0.20 eq.) andtriethylamine (0.03 ml; 0.24 mmol; 1.20 eq.). The reaction was stirredat room temperature for 24 h. Another 1 eq. of Boc₂O and 0.2 eq. of DMAPwere added and the reaction was stirred at room temperature overnight(total stirring time 40 h). The desired material was isolated by flashcolumn chromatography (KPNH column, 0 to 20% MeOH/EtOAc) to affordtert-butyl

[(3aR,5R,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-5-yl]methylcarbonate (5.30 mg, 8%) as a white solid (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 6.23 (d, J=6.3, 1H), 4.28 (dd, J=11.7, 2.3,1H), 4.16 (dd, J=11.8, 6.5, 1H), 4.06 (t, J=6.1, 1H), 3.93 (t, J=5.5,1H), 3.75 (t, J=7.0, 1H), 3.48 (dd, J=9.5, 5.2, 1H), 3.29-3.20 (m, 2H),1.46 (s, 9H), 1.16 (t, J=7.2, 3H);

MS (m/z): 348; 349 [M+H]⁺.

EXAMPLE 213aR,5S,6S,7R,7aR)-2-(ethylamino)-5-(fluoromethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 4

To(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(100.00 mg; 0.40 mmol; 1.00 eq.) in DCM (3.00 ml) was added(diethylamino)sulfur trifluoride (0.08 ml; 0.60 mmol; 1.50 eq.). Thereaction was stirred at room temperature for 2 h. The desired materialwas isolated by flash column chromatography (KPNH column, 0 to 15%MeOH/EtOAc 15CV). Product obtained, which was still not perfectly pure,was re-purified by flash column chromatography (KPNH column, 0 to 15%MeOH/EtOAc 15CV) again to afford(3aR,5S,6S,7R,7aR)-2-(ethylamino)-5-(fluoromethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(6.03 mg, 6%) as a white solid (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 6.26 (d, J=6.4, 1H), 4.59 (d, J=3.5, 1H), 4.49(d, J=3.5, 1H), 4.06 (dd, J=11.2, 5.2, 1H), 3.97-3.86 (m, 1H), 3.78-3.67(m, 1H), 3.51 (ddd, J=15.0, 9.3, 5.8, 1H), 3.29-3.16 (m, 2H), 1.20-1.12(m, 3H);

MS (m/z): 250; 251 [M+H]⁺.

EXAMPLE 223aR,5R,6S,7R,7aR)-5-[(benzyloxy)methyl]-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 8

To(3aR,4aR,8aS,9R,9aR)-2-(ethylamino)-7-phenyl-3a,4a,5,8a,9,9a-hexahydro[1,3]dioxino[4′,5′:5,6]pyrano[3,2-d][1,3]thiazol-9-ol(50.00 mg; 0.15 mmol; 1.00 eq.) in THF (1 mL) and molecular sieves (4 Å)was added sodium cyanoborohydride (37.36 mg; 0.59 mmol; 4.00 eq.) andthe reaction was stirred at room temperature for 1 h. The reaction wasthen cooled to 0° C. and hydrogen chloride (0.37 ml; 2.00 M; 0.74 mmol;5.00 eq.) was slowly added. Reaction was stirred at 0° C. for 15 min andthen stirred at room temperature overnight. Reaction mixture wasfiltered through cellite, washed with DCM, concentrated, diluted againwith DCM and washed with NaHCO₃. Organic layer was dried (Na₂SO₄),filtered, concentrated. The desired material was isolated by flashcolumn chromatography (KPNH column) to afford(3aR,5R,6S,7R,7aR)-5-[(benzyloxy)methyl]-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(12 mg, 24%) as a white solid (once lyophilized).

¹H NMR (500 MHz, cd₃od) δ 7.38-7.20 (m, 5H), 6.26 (d, J=6.4, 1H), 4.56(s, 2H), 4.07 (t, J=6.0, 1H), 3.93 (t, J=5.4, 1H), 3.73 (d, J=9.9, 2H),3.68-3.58 (m, 1H), 3.52 (dd, J=9.0, 5.3, 1H), 3.28-3.12 (m, 2H), 1.16(t, J=7.2, 3H);

MS (m/z): 338; 339 [M+H]⁺.

EXAMPLE 23Tert-butyl[(3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-2-yl]ethylcarbamate(compound no. 12)

To(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(100.00 mg; 0.40 mmol; 1.00 eq.), in tBuOH (2.00 ml) was addeddi-tert-butyl dicarbonate (105.47 mg; 0.48 mmol; 1.20 eq.). The reactionwas stirred at room temperature overnight. The desired product wasisolated by prep HPLC (0-15% B, 25 min, 220 nm, neutral conditions) toaffordtert-butyl[(3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-2-yl]ethylcarbamate(83.5 mg, 60%) as a white solid (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 6.09 (d, J=7.3, 1H), 4.13 (s, 1H), 4.04 (s,1H), 3.99-3.82 (m, 2H), 3.75 (d, J=11.6, 1H), 3.63 (m, 1H), 3.54 (m,1H), 3.44 (m, 1H), 1.53 (s, 9H), 1.18 (t, J=6.9, 3H);

MS (m/z): 348; 349 [M+H]⁺.

EXAMPLE 243aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-7-methoxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-6-ol(compound no. 15

To tert-butylethyl[(3aR,4aR,8aS,9R,9aR)-9-methoxy-7-phenyl-3a,4a,5,8a,9,9a-hexahydro[1,3]dioxino[4′,5′:5,6]pyrano[3,2-d][1,3]thiazol-2-yl]carbamate(30.00 mg; 0.07 mmol; 1.00 eq.) in DCM (0.5 mL) was addedtrifluoroacetic acid (50.00 μl; 0.67 mmol; 10.11 eq.). Reaction stirredat room temperature overnight. The desired material was isolated byflash column chromatography (KPNH column, 10-20% EtOAc/MeOH) to afford(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-7-methoxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-6-ol(13.7 mg, 78%) as a white solid (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 6.21 (d, J=6.4, 1H), 4.18 (t, J=5.8, 1H), 3.77(d, J=11.0, 1H), 3.66-3.54 (m, 4H), 3.54-3.49 (m, 3H), 3.29-3.17 (m,2H), 1.16 (t, J=7.2, 3H);

MS (m/z): 262; 263 [M+H]⁺.

EXAMPLE 253aR,5R,6S,7R,7aR)—N-ethyl-6,7-dimethoxy-5-(methoxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-2-amine(compound no. 13

Totert-butyl[(3aR,5R,6S,7R,7aR)-6,7-dimethoxy-5-(methoxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-2-yl]ethylcarbamate(22.30 mg; 0.06 mmol; 1.00 eq.) in DCM (0.5 mL) was addedtrifluoroacetic acid (10.00 μl; 0.13 mmol; 2.36 eq.) Reaction stirred atroom temperature for 24 h. The desired material was isolated by flashcolumn chromatography (KPNH column, 10-50% EtOAC/Hex) to afford(3aR,5R,6S,7R,7aR)—N-ethyl-6,7-dimethoxy-5-(methoxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-2-amine(13.1 mg, 79%) as a colorless oil (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 6.13 (d, J=6.5, 1H), 4.38 (dd, J=5.3, 3.8,1H), 3.86 (dd, J=3.3, 2.0, 1H), 3.58-3.51 (m, 2H), 3.50 (s, 3H), 3.47(dd, J=11.0, 6.0, 2H), 3.43 (s, 3H), 3.35 (s, 3H), 3.30-3.16 (m, 2H),1.16 (t, J=7.2, 3H);

MS (m/z): 290; 291 [M+H]⁺.

EXAMPLE 26 Tert-butyl{(3aR,5R,6S,7R,7aR)-5-[(benzyloxy)methyl]-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-2-yl}ethylcarbamate(compound no. 16)

To(3aR,5R,6S,7R,7aR)-5-[(benzyloxy)methyl]-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(100.00 mg; 0.30 mmol; 1.00 eq.) in tBuOH (2.00 ml) was addeddi-tert-butyl dicarbonate (70.94 mg; 0.33 mmol; 1.10 eq.). The reactionwas stirred at 37° C. overnight. The desired product was isolated byprep HPLC (neutral conditions, 20-60% B, 20 min, 220 nm) to affordtert-butyl{(3aR,5R,6S,7R,7aR)-5-[(benzyloxy)methyl]-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-2-yl}ethylcarbamate(48.4 mg, 37%) as a white solid (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 7.42-7.19 (m, 5H), 6.08 (d, J=6.6, 1H), 4.56(s, 2H), 4.13 (d, J=7.0, 1H), 4.04 (s, 1H), 3.99-3.83 (m, 2H), 3.70 (d,J=10.9, 1H), 3.67-3.52 (m, 3H), 1.54 (s, 9H), 1.18 (t, J=7.0, 3H);

MS (m/z): 439; 440 [M+H]⁺.

EXAMPLE 27(3aR,4aR,8aR,9R,9aR)-2-[(tert-butoxycarbonyl)(ethyl)amino]-7-phenyl-3a,4a,5,8a,9,9a-hexahydro[1,3]dioxino[4′,5′:5,6]pyrano[3,2-d][1,3]thiazol-9-ylmethanesulfonate(compound no. 29)

To tert-butylethyl[(3aR,4aR,8aS,9R,9aR)-9-hydroxy-7-phenyl-3a,4a,5,8a,9,9a-hexahydro[1,3]dioxino[4′,5′:5,6]pyrano[3,2-d][1,3]thiazol-2-yl]carbamate(199.00 mg; 0.46 mmol; 1.00 eq.) in DCM (2.00 ml) was addedmethanesulfonyl chloride (0.05 ml; 0.68 mmol; 1.50 eq.) andN,N-diethylethanamine (0.09 ml; 0.68 mmol; 1.50 eq.). The reaction wasstirred at room temperature for 2 h. The desired product was isolated byflash chromatography (KPNH, 20 to 75% EtOAc/Hex) to afford(3aR,4aR,8aR,9R,9aR)-2-[(tert-butoxycarbonyl)(ethyl)amino]-7-phenyl-3a,4a,5,8a,9,9a-hexahydro[1,3]dioxino[4′,5′:5,6]pyrano[3,2-d][1,3]thiazol-9-ylmethanesulfonate (90 mg, 38%) as a white solid (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 7.48 (s, 2H), 7.42-7.21 (m, 3H), 6.33 (d,J=7.4, 1H), 5.70 (s, 1H), 4.76-4.63 (m, 1H), 4.38-4.25 (m, 2H), 4.07 (s,1H), 3.98-3.73 (m, 4H), 3.08 (s, 3H), 1.55 (s, 9H), 1.19 (t, J=7.0, 3H);

MS (m/z): 515; 537 [M+Na]⁺.

EXAMPLE 283aR,5S,6S,7R,7aR)—N-(2-biphenyl-4-ylethyl)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxamide(compound no. 23

To(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxylicacid (70.00 mg; 0.27 mmol; 1.00 eq.) in DMSO (1.00 ml) was added1-hydroxylbenzotriazole (72.13 mg; 0.53 mmol; 2.00 eq.),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (102.33mg; 0.53 mmol; 2.00 eq.) and 2-(4-biphenyl)ethylamine (105.30 mg; 0.53mmol; 2.00 eq.). The reaction was stirred at room temperature overnight.The desired material was isolated by flash column chromatography (KPNHcolumn, 0-20% MeOH/EtOAc) to afford(3aR,5S,6S,7R,7aR)—N-(2-biphenyl-4-ylethyl)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxamide(20.9 mg, 18%) as a white solid (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 7.56 (dd, J=20.6, 7.9, 4H), 7.41 (t, J=7.7,2H), 7.30 (d, J=8.0, 3H), 6.21 (d, J=6.2, 1H), 4.15 (t, J=5.6, 1H), 4.04(t, J=4.7, 1H), 3.91 (d, J=8.7, 1H), 3.77 (dd, J=8.3, 3.9, 1H), 3.48 (t,J=6.2, 2H), 3.29-3.16 (m, 2H), 2.85 (t, J=7.1, 2H), 1.16 (t, J=7.2, 3H);

MS (m/z): 442; 443 [M+H]⁺.

EXAMPLE 293aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-N,N-dimethyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxamide(compound no. 28

To(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxylicacid (70.00 mg; 0.27 mmol; 1.00 eq.) in DMSO (1.00 ml) was added1-hydroxylbenzotriazole (72.13 mg; 0.53 mmol; 2.00 eq.),N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (102.33mg; 0.53 mmol; 2.00 eq.), dimethylamine hydrochloride (43.53 mg; 0.53mmol; 2.00 eq.) and n,n-diisopropylethylamine (0.09 ml; 0.53 mmol; 2.00eq.). The reaction was stirred at room temperature overnight. Thedesired material was isolated by prep HPLC (0% B for 10 min, then to 30%B for 10 min, 220 nm, 0.1% TFA) to afford(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-N,N-dimethyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxamide(6.4 mg, 6%) as a white solid (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 6.61 (d, J=4.6, 1H), 4.54 (d, J=6.8, 1H), 4.25(s, 1H), 3.99 (s, 2H), 3.79-3.66 (m, 2H), 3.44 (s, 3H), 3.27-3.18 (m,3H), 1.29 (t, J=7.2, 3H);

MS (m/z): 289; 290 [M+H]⁺.

EXAMPLE 303aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-N-phenyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxamide(compound no. 31

In a similar manner to EXAMPLE 28,(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-N-phenyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxamidewas obtained from(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxylicacid (100.00 mg; 0.38 mmol; 1.00 eq.) and aniline (0.05 ml; 0.57 mmol;1.50 eq.). Isolated 9.3 mg (5%) of the title compound as a white solid.

¹H NMR (500 MHz, CD₃OD) δ 7.60 (d, J=8.6, 2H), 7.33 (t, J=7.6, 2H), 7.15(d, J=7.3, 1H), 6.69 (s, 1H), 4.30 (s, 1H), 4.25 (d, J=8.2, 1H), 3.97(d, J=28.3, 2H), 3.45 (m, 2H), 1.31 (t, J=7.3, 3H);

MS (m/z): 337; 338 [M+H]⁺.

EXAMPLE 313aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-N-[2-(4-phenoxyphenyl)ethyl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxamide(compound no. 33

In a similar manner to EXAMPLE 28,(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-N-[2-(4-phenoxyphenyl)ethyl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxamidewas obtained from(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxylicacid (100.00 mg; 0.38 mmol; 1.00 eq.) and 2-(4-phenoxyphenyl)ethanamine(0.11 ml; 0.57 mmol; 1.50 eq.). Isolated 7.3 mg (4%) of the titlecompound as a white solid.

¹H NMR (500 MHz, CD₃OD) δ 8.02 (s, 1H), 7.23 (t, J=7.7, 2H), 7.12 (d,J=8.3, 2H), 6.98 (t, J=7.0, 1H), 6.83 (dd, J=16.6, 8.5, 3H), 6.46 (s,1H), 4.19 (s, 1H), 3.93 (d, J=8.3, 1H), 3.89 (s, 1H), 3.74 (s, 1H),3.43-3.26 (m, 4H), 2.72 (t, J=7.2, 2H), 1.19 (t, J=7.3, 3H);

MS (m/z): 458; 458 [M]⁺.

EXAMPLE 32Methyl-(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxylate(compound no. 42)

To(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxylicacid (100.00 mg; 0.38 mmol; 1.00 eq.) in methanol (1.00 ml) was addedthionyl chloride (0.05 ml; 0.76 mmol; 2.00 eq.). The reaction wasstirred at room temperature for 1 h. The desired material was isolatedby flash column chromatography (silica gel column, 0 to 50% MeOH/DCM,15CV) to affordmethyl(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxylate(81.4 mg, 77%) as an off white solid (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 6.30 (d, J=4.8, 1H), 4.24 (d, J=5.6, 1H), 4.15(t, J=4.6, 1H), 4.08 (t, J=4.5, 1H), 3.98 (t, J=5.2, 1H), 3.75 (s, 3H),3.43-3.32 (m, 2H), 1.23 (t, J=7.3, 3H);

MS (m/z): 276; 277 [M+H]⁺.

EXAMPLE 333aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-N-methoxy-N-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxamide(compound no. 45

To(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxylicacid (2.00 g; 7.63 mmol; 1.00 eq.) in DMF (10.00 ml) was addedn,o-dimethylhydroxylamine hydrochloride (1115.70 mg; 11.44 mmol; 1.50eq.), n,n-di-iso-propylethylamine (3.33 ml; 19.06 mmol; 2.50 eq.) andthen 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide(3.37 ml; 11.44 mmol; 1.50 eq.) (T3P). Reaction was stirred at roomtemperature for 2 h. The reaction mixture was heated to 65° C. to fullydissolve starting material. Reaction was then stirred at roomtemperature overnight, concentrated to reduce volume of DMF to 2-3 mL,and the desired product was isolated by flash chromatography (silica gelcolumn, 0 to 50% MeOH/DCM) to afford(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-N-methoxy-N-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxamide(1.23 g, 52%) as a light yellow solid (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 6.26 (d, J=6.0, 1H), 4.60 (s, 1H), 4.11 (s,1H), 4.00 (s, 2H), 3.77 (s, 3H), 3.36-3.33 (m, 3H), 3.28-3.18 (m, 2H),1.17 (t, J=7.2, 3H);

MS (m/z): 305; 306 [M+H]⁺.

EXAMPLE 343aR,5R,6R,7R,7aR)-2-(ethylamino)-6-hydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-7-ylmethanesulfonate (compound no. 46

To(3aR,4aR,8aR,9R,9aR)-2-[(tert-butoxycarbonyl)(ethyl)amino]-7-phenyl-3a,4a,5,8a,9,9a-hexahydro[1,3]dioxino[4′,5′:5,6]pyrano[3,2-d][1,3]thiazol-9-ylmethanesulfonate (30.00 mg; 0.06 mmol; 1.00 eq.) in DCM (100.00 μl) wasadded trifluoroacetic acid (10.00 μl; 0.13 mmol; 2.31 eq.). The reactionwas stirred at room temperature for 3 h. The desired product wasisolated by flash chromatography (KPNH, 0 to 50% MeOH/DCM). To afford(3aR,5R,6R,7R,7aR)-2-(ethylamino)-6-hydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-7-ylmethanesulfonate (19.2 mg, 64%) as a white solid (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 6.33 (d, J=6.4, 1H), 4.89 (t, J=5.6, 1H), 4.27(t, J=6.1, 1H), 3.81-3.70 (m, 2H), 3.70-3.61 (m, 1H), 3.36-3.33 (m, 2H),3.25 (dd, J=13.9, 6.7, 1H), 3.22-3.18 (m, 3H), 1.16 (dd, J=8.8, 5.7,3H);

MS (m/z): 326; 327 [M+H]⁺.

EXAMPLE 353aR,5R,6S,7R,7aR)-5-[(benzylamino)methyl]-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 48

To(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carbaldehyde(76.00 mg; 0.31 mmol; 1.00 eq.) in methanol (1.00 ml) was addedbenzylamine (0.05 ml; 0.46 mmol; 1.50 eq.), and sodium cyanoborohydride(9.70 mg; 0.15 mmol; 0.50 eq.) in 0.5 mL MeOH. The reaction was stirredat room temperature for 2 h. The desired product was isolated by prepHPLC (0% B for 10 min, then 0 to 30% B over 10 min, 0.1% TFA, 220 nm) toafford(3aR,5R,6S,7R,7aR)-5-[(benzylamino)methyl]-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(12.2 mg, 12%) as a white solid (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 7.57-7.38 (m, 5H), 6.63 (d, J=6.4, 1H), 4.29(d, J=2.6, 2H), 4.24 (dd, J=11.9, 5.1, 1H), 4.02 (t, J=9.1, 1H), 3.90(t, J=6.6, 1H), 3.55 (d, J=13.3, 1H), 3.44 (dt, J=13.0, 6.7, 3H), 3.26(dd, J=13.2, 9.7, 1H), 1.30 (t, J=7.3, 3H);

MS (m/z): 337; 338 [M+H]⁺.

EXAMPLE 36Methyl-[(3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-2-yl]ethylcarbamate(compound no. 49)

To(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(100.00 mg; 0.40 mmol; 1.00 eq.) in dry THF (12 mL) was addedN-ethyl-N-isopropylpropan-2-amine (0.09 ml; 0.52 mmol; 1.30 eq.). Themixture was cooled to 0° C. then methyl chloroformate (0.05 ml, 0.60mmol, 1.50 eq.) was added dropwise. The reaction was stirred at roomtemperature for 2 h. The desired product was isolated by flashchromatography (KPNH column, 10 to 100% MeOH/DCM) to affordmethyl[(3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-2-yl]ethylcarbamate(19.6 mg, 16%) as a white solid (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 6.13 (d, J=6.8, 1H), 4.20-4.14 (m, 1H), 4.06(t, J=4.7, 1H), 3.98 (ddd, J=28.5, 13.7, 6.9, 2H), 3.83 (s, 3H),3.78-3.73 (m, 1H), 3.64 (dd, J=12.1, 6.2, 1H), 3.56 (dd, J=9.2, 4.5,1H), 3.47-3.40 (m, 1H), 1.19 (t, J=7.0, 3H);

MS (m/z): 306; 307 [M+H]⁺.

EXAMPLE 373aR,5R,6S,7R,7aR)-5-[(dimethylamino)methyl]-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 51

To(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carbaldehyde(40.00 mg; 0.16 mmol; 1.00 eq.) in MeOH (1.00 ml) was addeddimethylamine hydrochloride (15.89 mg; 0.19 mmol; 1.20 eq.), and sodiumcyanoborohydride (5.10 mg; 0.08 mmol; 0.50 eq.) in 0.5 mL MeOH. Thereaction was stirred at room temperature for 15 min. The desired productwas isolated by flash chromatography (KPNH column, 0 to 100% MeOH/DCM,15CV) to afford(3aR,5R,6S,7R,7aR)-5-[(dimethylamino)methyl]-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(9.6 mg, 21%) as a white solid (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 6.24 (d, J=6.5, 1H), 4.11 (t, J=5.8, 1H), 3.98(t, J=4.8, 1H), 3.71 (td, J=9.0, 2.0, 1H), 3.25 (ddd, J=18.0, 10.1, 6.2,3H), 2.71 (dd, J=13.3, 2.1, 1H), 2.51 (dd, J=13.2, 9.0, 1H), 2.28 (s,6H), 1.16 (t, J=7.2, 3H);

MS (m/z): 275; 276 [M+H]⁺.

EXAMPLE 381-[(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-5-yl]-3-phenylpropan-1-one(compound no. 59)

To(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-N-methoxy-N-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxamide(100.00 mg; 0.33 mmol; 1.00 eq.) in THF (1.00 ml) was added dropwisephenethyl magnesium bromide (1.96 ml; 1.00 M; 1.96 mmol; 6.00 eq.). Thereaction was stirred at room temperature for 3 h, then phenethylmagnesium bromide (1.96 ml; 1.00 M; 1.96 mmol; 6.00 eq.) was slowlyadded again and it was continued to stir at room temperature overnight.Another phenethyl magnesium bromide (1.96 ml; 1.00 M; 1.96 mmol; 6.00eq.) was added and the reaction was stirred at room temperatureovernight. It was added water, concentrated, added more water, andlyophilized. It was used half of crude in next step. The other half waspurified by prep HPLC (10% B for 5 min then up to 40% B over 20 min,0.1% TFA, 220 nm) to afford1-[(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-5-yl]-3-phenylpropan-1-one(12.7 mg, 8%) as a white solid (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 7.31-7.08 (m, 5H), 6.52 (d, J=6.3, 1H), 4.29(s, 1H), 4.15-4.03 (m, 2H), 3.92 (s, 1H), 3.41 (d, J=6.6, 2H), 2.92 (dd,J=18.5, 5.9, 4H), 1.28 (t, J=7.3, 3H);

MS (m/z): 350; 351 [M+H]⁺.

EXAMPLE 393aR,5R,6S,7R,7aR)-2-Ethylamino-5-((S)-1-hydroxy-3-phenyl-propyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol(compound no. 53

To crude1-[(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-5-yl]-3-phenylpropan-1-one(200.00 mg; 0.57 mmol; 1.00 eq.) in MeOH (3.00 ml) was added sodiumborohydride (21.59 mg; 0.57 mmol; 1.00 eq.). Reaction was stirred atroom temperature for 30 min. The desired product was isolated by prepHPLC (0% B for 10 min, then up to 30% B for 10 min, 0.1% TFA, 220 nm) toafford(3aR,5R,6S,7R,7aR)-2-Ethylamino-5-((S)-1-hydroxy-3-phenyl-propyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol(1.9 mg, 1%) as a white solid (once lyophilized).

¹H NMR (500 MHz, CD₃OD) δ 7.29-7.18 (m, 4H), 7.15 (t, J=7.2, 1H), 6.62(d, J=6.5, 1H), 4.21 (t, J=6.4, 1H), 3.91 (t, J=6.1, 1H), 3.87 (m, 2H),3.83-3.76 (m, 1H), 3.50-3.37 (m, 2H), 2.85-2.74 (m, 1H), 2.71-2.56 (m,1H), 1.92 (d, J=9.1, 1H), 1.78 (s, 1H), 1.28 (t, J=7.3, 3H);

MS (m/z): 352; 353 [M+H]⁺.

Arbitrary assigned stereochemistry of 6-alcohol.

EXAMPLE 403aR,5R,6S,7R,7aR)-2-Ethylamino-5-((R)-1-hydroxy-3-phenyl-propyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol(compound no. 54

(3aR,5R,6S,7R,7aR)-2-Ethylamino-5-((R)-1-hydroxy-3-phenyl-propyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diolwas the other isomer isolated from1-[(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-5-yl]-3-phenylpropan-1-one(1.5 mg, 1%).

¹H NMR (500 MHz, CD₃OD) δ 7.19-7.08 (m, 4H), 7.05 (t, J=7.2, 1H), 6.49(d, J=6.7, 1H), 4.15 (t, J=6.3, 1H), 3.83 (t, J=5.5, 1H), 3.75 (d,J=9.5, 1H), 3.64-3.56 (m, 1H), 3.56-3.48 (m, 1H), 3.37-3.26 (m, 2H),2.82-2.66 (m, 1H), 2.55 (ddd, J=13.5, 9.7, 6.9, 1H), 1.86-1.56 (m, 2H),1.18 (t, J=7.3, 3H);

MS (m/z): 352; 353 [M+H]⁺.

Arbitrary assigned stereochemistry of 6-alcohol.

EXAMPLE 411-[(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-5-yl]-4-phenylbutan-1-one(compound no. 60)

In a similar manner to EXAMPLE 38,1-[(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-5-yl]-4-phenylbutan-1-onewas obtained from1-[(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-N-methoxy-N-methyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-5-carboxamide(100.00 mg; 0.33 mmol; 1.00 eq.) and 3-(phenyl)propyl magnesium bromide(1.96 ml; 1.00 M; 1.96 mmol; 6.00 eq.) as a white sticky solid (oncelyophilized) (16.5 mg, 11%).

¹H NMR (500 MHz, CD₃OD) δ 7.26 (t, J=7.6, 2H), 7.17 (d, J=6.7, 3H), 6.53(d, J=6.2, 1H), 4.29 (s, 1H), 4.09 (d, J=7.4, 1H), 4.05 (s, 1H), 3.91(s, 1H), 3.41 (d, J=7.1, 2H), 2.62 (t, J=7.5, 4H), 1.91 (dd, J=15.1,7.4, 2H), 1.29 (t, J=7.3, 3H);

MS (m/z): 364; 365 [M+H]⁺.

EXAMPLE 423aR,5R,6S,7R,7aR)-2-(ethylamino)-5-((R)1-hydroxy-4-phenylbutyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 55

In a similar manner to EXAMPLE 39,(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-((R)1-hydroxy-4-phenylbutyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diolwas obtained as a colorless oil from1-[(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-5-yl]-3-phenylpropan-1-one(200.00 mg; 0.57 mmol; 1.00 eq.) (4 mg, 2%).

¹H NMR (500 MHz, CD₃OD) δ 7.39-7.03 (m, 5H), 6.59 (d, J=6.6, 1H), 4.23(s, 1H), 3.92 (s, 2H), 3.62 (d, J=3.2, 2H), 3.51-3.37 (m, 2H), 2.81-2.53(m, 2H), 1.87 (s, 1H), 1.80-1.44 (m, 3H), 1.28 (t, J=7.3, 3H);

MS (m/z): 366; 367 [M+H]⁺.

Arbitrary assigned stereochemistry of 6-alcohol.

EXAMPLE 433aR,5R,6S,7R,7aR)-2-(ethylamino)-5-((S)1-hydroxy-4-phenylbutyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(compound no. 56

In a similar manner to EXAMPLE 38,(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-((S)1-hydroxy-4-phenylbutyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diolwas obtained as a colorless oil from1-[(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-5-yl]-3-phenylpropan-1-one(200.00 mg; 0.57 mmol; 1.00 eq.) (2.4 mg, 1%).

¹H NMR (500 MHz, CD₃OD) δ 7.24 (d, J=7.6, 3H), 7.19 (s, 2H), 6.61 (d,J=6.5, 1H), 4.18 (t, J=6.5, 1H), 3.90 (s, 2H), 3.84-3.70 (m, 1H),3.51-3.38 (m, 3H), 2.64 (s, 2H), 1.78 (dd, J=16.7, 9.3, 1H), 1.58 (d,J=63.1, 3H), 1.28 (t, J=7.2, 3H);

MS (m/z): 366; 367 [M+H]⁺.

Arbitrary assigned stereochemistry of 6-alcohol.

EXAMPLE 44Phenyl-[(3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-2-yl]ethylcarbamate(compound no. 63)

In a similar manner to EXAMPLE 36,phenyl[(3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-2-yl]ethylcarbamatewas obtained from(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(100.00 mg; 0.40 mmol; 1.00 eq.) and phenyl chloridocarbonate (0.05 ml;0.40 mmol; 1.00 eq.). 96 mg (65%) of the title compound were isolated asa white solid.

¹H NMR (500 MHz, CD₃OD) δ 7.43 (t, J=7.8, 2H), 7.28 (t, J=7.4, 1H), 7.18(d, J=8.4, 2H), 6.17 (d, J=6.9, 1H), 4.27-4.19 (m, 1H), 4.19-4.10 (m,2H), 4.09 (t, J=4.7, 1H), 3.76 (dd, J=12.0, 2.2, 1H), 3.64 (dd, J=12.0,6.2, 1H), 3.58 (dd, J=9.0, 4.3, 1H), 3.51-3.44 (m, 1H), 1.34 (t, J=6.9,3H);

MS (m/z): 368; 369 [M+H]⁺.

EXAMPLE 45benzyl[(3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-2-yl]ethylcarbamate(compound no. 62)

In a similar manner to EXAMPLE 36,benzyl[(3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazol-2-yl]ethylcarbamatewas obtained from(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(100.00 mg; 0.40 mmol; 1.00 eq.) benzyl chloridocarbonate (0.06 ml, 0.40mmol; 1.00 eq.). 69 mg (45%) of the title compound were isolated as awhite solid.

¹H NMR (500 MHz, CD₃OD) δ 7.43 (t, J=7.8, 2H), 7.28 (t, J=7.4, 1H), 7.18(d, J=8.4, 2H), 6.17 (d, J=6.9, 1H), 4.27-4.19 (m, 1H), 4.19-4.10 (m,2H), 4.09 (t, J=4.7, 1H), 3.76 (dd, J=12.0, 2.2, 1H), 3.64 (dd, J=12.0,6.2, 1H), 3.58 (dd, J=9.0, 4.3, 1H), 3.51-3.44 (m, 1H), 1.34 (t, J=6.9,3H);

MS (m/z): 382; 383 [M+H]⁺.

EXAMPLE 46N-((3aR,5R,6S,7R,7aR)-6,7-Dihydroxy-5-hydroxymethyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)-N-ethyl-3,3-dimethyl-butyramide(compound no. 104)

N-((3aR,5R,6S,7R,7aR)-6,7-dihydroxy-5-hydroxymethyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)-N-ethyl-3,3-dimethyl-butyramidewas obtained from(3aR,5R,6S,7R,7aR)-2-Ethylamino-5-hydroxymethyl-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol(200.00 mg; 0.81 mmol; 1.00 eq.) and 3,3-dimethylbutyric acid (0.12 ml;0.97 mmol; 1.20 eq.). 40.0 mg (10.8%) of the title compound wereisolated as a white solid.

¹H NMR (500 MHz, CD₃OD) δ 6.26 (d, J=7.1, 1H), 4.27-4.18 (m, 1H), 4.07(t, J=5.1, 1H), 3.99 (dt, J=14.8, 7.7, 2H), 3.78 (dd, J=12.0, 2.2, 1H),3.67 (dd, J=12.1, 6.2, 1H), 3.57 (dd, J=9.0, 4.7, 1H), 3.53-3.46 (m,1H), 2.62 (q, J=16.1, 2H), 1.29 (t, J=7.1, 3H), 1.09 (s, 9H);

MS (m/z): 346; 347 [M+H]⁺.

EXAMPLE 472-Ethylamino-5-[4-(1-hydroxy-1-phenyl-ethyl)-[1,2,3]triazol-1-ylmethyl]-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol(compound no. 67)

In a 10 mL rb flask was added(3aR,5R,6S,7R,7aR)-5-(azidomethyl)-2-(ethylamino)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d][1,3]thiazole-6,7-diol(40 mg, 0.15 mmol, 1.00 eq.), copper turnings (66 mg; 1.05 mmol; 7.00eq.) and copper(11)sulfate pentahydrate (7.5 mg; 0.03 mmol; 0.20 eq.).The flask was evacuated and filled with nitrogen. This procedure wasrepeated twice before ethanol (0.5 ml)/water (0.7ml)/2-methylpropan-2-ol (1.3 ml) and 2-phenylbut-3-yn-2-ol (22 mg; 0.45mmol; 3.00 eq.) was added into the mixture and stirred for 24 h to getthe reaction completed. Product formation was confirmed by LCMS. Thesolution was diluted with 2 mL H₂O, dried and separated with mass basedprep HPLC to afford the desired product.

Yield: 21% (16 mg, off-white solid).

The following compounds were prepared in a similar manner.

Compound No. 95

400 MHz, DMSO-d6: δ 10.41 (s, 1H), 7.37-8.09 (m, 5H), 6.52 (s, 1H),5.70-5.79 (m, 4H), 4.32-4.71 (m, 3H), 4.04-4.06 (m, 1H), 3.74-3.78 (m,2H), 3.25-3.44 (m, 3H), 1.05 (t, J=7.13 Hz, 3H).

LCMS: (Method A) 498.0 (M+H), RT 2.65 min, 99.1% (Max), 99.3% (254 nm).

HPLC: (Method A) RT 2.64 min, 99.41% (Max), 99.21% (254 nm).

Compound No. 65

400 MHz, DMSO-d6: δ 7.88 (s, 1H), 5.81 (s, 1H), 5.17 (s, 2H), 4.50-4.71(m, 2H), 4.11-4.14 (m, 1H), 3.36-3.44 (m, 7H), 2.17 (s, 3H), 1.99 (s,3H), 1.81 (s, 3H), 1.14 (t, J=7.12 Hz, 3H).

LCMS: (Method A) 422.2 (M+H-TFA), RT 1.86 min, 91.11% (Max), 93.37% (220nm).

Compound No. 96

400 MHz, DMSO-d6: δ 10.49 (s, 1H), 10.18 (s, 1H), 8.04 (s, 1H),6.49-6.50 (m, 1H), 5.84 (s, 2H), 5.30-5.36 (m, 2H), 4.51-4.75 (m, 2H),4.11-4.14 (m, 1H), 3.80-3.90 (m, 2H), 3.41-3.48 (m, 2H), 2.50 (s, 1H),2.11 (s, 1H), 1.13 (s, 1H).

LCMS: (Method B) 409.3 (M+H), RT 2.82 min, 95.76% (Max), 93.66% (254nm).

HPLC: (Method A) RT 2.82 min, 96.99% (Max), 96.51% (220 nm).

Compound No. 97

400 MHz, DMSO-d6: δ 10.42 (s, 1H), 10.08 (s, 1H), 8.07 (s, 1H),7.26-7.85 (m, 5H), 6.50 (d, J=6.52 Hz, 1H), 5.84 (s, 2H), 5.50 (s, 2H),4.72-4.77 (m, 1H), 4.54-4.60 (m, 1H), 4.10-4.13 (m, 1H), 3.50-3.88 (m,2H), 3.34-3.37 (m, 2H), 1.16 (t, J=Hz, 3H).

LCMS: (Method A) 462.0 (M+H), RT 1.46 min, 96.39% (Max), 95.56% (254nm).

HPLC: (Method B) RT 3.61 min, 98.15% (Max), 97.65% (220 nm).

Compound No. 66

400 MHz, DMSO-d6: δ 8.12 (s, 1H), 7.90 (s, 1H), 6.76-6.77 (m, 2H), 6.16(s, 1H), 5.96-5.97 (m, 2H), 5.23-5.27 (m, 2H), 5.12 (s, 2H), 4.62-4.66(m, 1H), 4.38-4.44 (m, 1H), 3.97 (t, J=5.92 Hz, 1H), 3.79-3.82 (m, 1H),3.65-3.69 (m, 1H), 3.10-3.15 (m, 2H), 1.04 (t, J=7.18 Hz, 3H).

LCMS: (Method A) 479.0 (M+H), RT 2.11 min, 96.40% (Max), 97.40% (220nm).

HPLC: (Method A) RT 2.08 min, 96.98% (Max), 96.57% (220 nm).

Compound No. 67

400 MHz, DMSO-d6: δ 10.42 (s, 1H), 10.10 (s, 1H), 7.78 (s, 1H),7.18-7.44 (m, 5H), 6.52-6.53 (m, 1H), 5.85-5.87 (m, 3H), 4.68-4.72 (m,1H), 4.52-4.54 (m, 1H), 4.11-4.14 (m, 1H), 3.87-3.89 (m, 1H), 3.78-3.81(m, 1H), 3.34-3.40 (m, 2H), 1.79 (s, 3H), 1.14 (t, J=7.04 Hz, 3H).

LCMS: (Method A) 420.3 (M+H-TFA), RT 2.21 min, 91.36% (Max), 91.49% (220nm).

HPLC: (Method A) RT 2.28 min, 95.50% (Max), 95.05% (220 nm).

Compound No. 68

400 MHz, DMSO-d6: δ 7.73 (s, 1H), 7.23-7.39 (m, 5H), 6.17 (s, 1H),5.94-5.97 (m, 1H), 5.75-5.79 (m, 1H), 5.21 (s, 2H), 4.60-4.64 (m, 1H),4.40-4.42 (m, 1H), 3.99 (s, 1H), 3.81-3.82 (m, 1H), 3.12-3.73 (m, 1H),3.46-3.48 (m, 1H), 3.40-3.42 (m, 1H), 3.12-3.24 (m, 2H), 1.04 (t, J=Hz,J=7.18 Hz, 3H).

LCMS: (Method A) 406.2 (M+H), RT 1.97 min, 96.77% (Max), 96.00% (220nm).

HPLC: (Method A) RT 1.98 min, 96.70% (Max), 96.73% (220 nm).

Compound No. 69

400 MHz, DMSO-d6: δ 8.12-8.21 (m, 3H), 7.93 (s, 1H), 7.45-7.47 (m, 2H),7.43-7.43 (m, 2H), 7.18-7.21 (m, 2H), 6.05 (d, J=6.20 Hz, 1H), 5.64 (s,2H), 5.09-5.15 (m, 2H), 4.53-4.57 (m, 1H), 4.29-4.33 (m, 1H), 3.90-3.93(m, 1H), 3.76-3.77 (m, 1H), 3.62 (s, 1H), 3.04-3.09 (m, 2H), 1.00 (t,J=7.16 Hz, 3H).

LCMS: (Method A) 479.3 (M+H), RT 3.54 min, 99.26% (Max), 99.20% (220nm).

HPLC: (Method A) RT 3.63 min, 98.78% (Max), 99.17% (220 nm).

Compound No. 98

400 MHz, DMSO-d6: δ 8.58 (s, 1H), 8.28 (s, 1H), 8.00-8.21 (m, 1H),7.58-7.71 (m, 3H), 7.35-7.45 (m, 5H), 6.51 (s, 1H), 6.25 (s, 2H),5.23-5.42 (m, 2H), 4.73-4.77 (m, 1H), 4.53-4.55 (m, 1H), 4.00-4.02 (m,1H), 3.39-3.41 (m, 1H), 3.13-3.14 (m, 2H), 1.04 (t, J=7.12 Hz, 3H).

LCMS: (Method A) 555.0 (M+H), RT 3.802 min, 97.82% (Max), 98.36% (254nm).

HPLC: (Method A) RT 3.78 min, 99.12% (Max), 98.58% (254 nm).

Compound No. 99

400 MHz, DMSO-d6: δ 10.33 (s, 1H), 10.19 (s, 1H), 7.55 (s, 1H),7.23-7.33 (m, 2H), 6.49 (d, J=6.52 Hz, 1H), 5.79 (s, 2H), 4.63-4.67 (m,1H), 3.79-4.49 (m, 4H), 1.23-1.35 (m, 2H), 1.12-1.16 (m, 2H), 1.05 (t,J=7.00 Hz, 3H).

LCMS: (Method A) 416.0 (M+H), RT 2.98 min, 94.30% (Max), 94.52% (220nm).

HPLC: (Method A) RT 2.97 min, 95.23% (Max), 95.12% (220 nm).

Compound No. 100

400 MHz, DMSO-d6: δ 10.23 (s, 1H), 7.82 (s, 1H), 7.13-7.30 (m, 5H), 6.53(s, 1H), 5.62 (s, 2H), 4.10-4.69 (m, 3H), 3.24-3.81 (m, 5H), 2.50-2.50(m, 2H), 2.03-2.06 (m, 2H), 1.69-1.71 (m, 2H), 1.53-1.55 (m, 2H), 1.10(t, J=7.20 Hz, 3H).

LCMS: (Method A) 444.3 (M+H), RT 3.35 min, 98.21% (Max), 97.86% (254nm).

HPLC: (Method A) RT 3.35 min, 98.84% (Max), 98.87% (220 nm).

Compound No. 70

400 MHz, DMSO-d6: δ 8.12 (s, 1H), 8.01 (d, J=3.76 Hz, 1H), 7.56-7.59 (m,2H), 7.41-7.47 (m, 1H), 7.36-7.41 (m, 3H), 6.13-6.13 (m, 1H), 5.28-5.32(m, 2H), 4.69-4.73 (m, 1H), 4.47-4.53 (m, 1H), 3.96-3.99 (m, 1H),3.79-3.81 (m, 1H), 3.64-3.64 (m, 1H), 3.14 (q, J=7.08 Hz, 2H), 1.04 (t,J=6.64 Hz, 3H).

LCMS: (Method A) 474.0 (M+H), RT 2.88 min, 96.13% (Max), 95.61% (220nm).

HPLC: (Method A) RT 3.05 min, 96.05% (Max), 95.31% (220 nm).

Compound No. 71

400 MHz, DMSO-d6: δ 7.75 (s, 1H), 7.12-7.16 (m, 2H), 6.78-6.80 (m, 2H),6.60-6.63 (m, 1H), 6.14 (s, 1H), 5.26 (s, 2H), 4.53-4.63 (m, 3H),4.37-4.39 (m, 1H), 3.11-3.96 (m, 6H), 2.92 (s, 3H), 2.49 (s, 1H), 1.04(t, J=7.12 Hz, 3H).

LCMS: (Method A) 419.3 (M+H), RT 1.72 min, 98.06% (Max), 98.21% (220nm).

HPLC: (Method A) RT 1.72 min, 98.02% (Max), 97.98% (220 nm).

Compound No. 72

400 MHz, DMSO-d6: δ 8.12 (s, 1H), 7.23-7.28 (m, 2H), 7.13-7.15 (m, 2H),7.03-7.06 (m, 1H), 6.21-6.35 (m, 1H), 5.29-5.40 (m, 2H), 5.15 (s, 2H),4.68-4.72 (m, 1H), 4.50-4.52 (m, 1H), 4.01-4.02 (m, 1H), 3.76-3.82 (m,2H), 3.17-3.19 (m, 2H), 1.07 (t, J=7.16 Hz, 3H).

LCMS: (Method A) 484.0 (M+H), RT. 3.19 min, 97.31% (Max), 97.72% (220nm).

HPLC: (Method A) RT 3.22 min, 98.55% (Max), 98.65% (220 nm).

Compound No. 73

400 MHz, DMSO-d6: δ 8.12 (s, 1H), 7.36-7.56 (m, 4H), 6.28 (s, 1H), 5.40(s, 2H), 5.20 (s, 2H), 4.68-4.72 (m, 1H), 4.46-4.52 (m, 1H), 4.01-4.11(m, 1H), 3.75-3.83 (m, 2H), 3.32 (s, 1H), 3.17-3.17 (m, 2H), 1.06 (t,J=7.16 Hz, 3H).

LCMS: (Method A) 431.3 (M+H), RT 2.55 min, 97.26% (Max), 97.44% (220nm).

HPLC: (Method A) RT 2.58 min, 96.52% (Max), 96.44% (220 nm).

Compound No. 74

400 MHz, DMSO-d6: δ 8.10-8.13 (m, 1H), 7.31-7.34 (m, 2H), 7.06 (d,J=8.96 Hz, 2H), 6.19 (s, 1H), 5.32 (s, 2H), 5.12 (s, 2H), 4.67-4.70 (m,1H), 4.44-4.49 (m, 1H), 4.00 (t, J=5.20 Hz, 1H), 3.81 (d, J=4.40 Hz,1H), 3.70-3.72 (m, 1H), 3.12-3.14 (m, 2H), 1.05 (t, J=7.20 Hz, 3H).

LCMS: (Method A) 422.0 (M+H), RT 2.09 min, 98.95% (Max), 98.60% (220nm).

HPLC: (Method A) RT 2.13 min, 98.35% (Max), 98.44% (220 nm).

Compound No. 75

400 MHz, DMSO-d6: δ 8.10 (s, 1H), 7.21-7.25 (m, 1H), 6.87-6.96 (m, 3H),6.24 (s, 1H), 5.40-5.43 (m, 2H), 5.16-5.19 (m, 1H), 4.71 (d, J=2.28 Hz,2H), 4.45-4.68 (m, 3H), 3.99-4.02 (m, 1H), 3.73-3.83 (m, 3H), 3.16-3.37(m, 3H), 1.04 (t, J=Hz, J=7.18 Hz, 3H).

LCMS: (Method A) 436.3 (M+H), RT 2.02 min, 98.91% (Max), 98.75% (220nm).

HPLC: (Method A) RT 2.13 min, 98.60% (Max), 98.98% (220 nm).

Compound No. 76

400 MHz, DMSO-d6: δ 8.13 (s, 1H), 8.08 (s, 1H), 7.20-7.24 (m, 1H),6.86-6.98 (m, 3H), 6.17 (d, J=5.68 Hz, 2H), 5.10-5.28 (m, 5H), 4.66-4.70(m, 2H), 4.43-4.49 (m, 1H), 3.97-4.00 (m, 1H), 3.41-3.74 (m, 2H),3.11-3.41 (m, 3H), 1.30 (d, J=6.44 Hz, 3H), 1.06 (t, J=Hz, 3H).

LCMS: (Method A) 450.0 (M+H), RT 2.26 min, 95.99% (Max), 97.05% (220nm).

HPLC: (Method A) RT 2.27 min, 97.61% (Max), 97.24% (220 nm).

Compound No. 101

400 MHz, DMSO-d6: δ 8.14 (s, 1H), 6.95-7.08 (m, 1H), 6.51-6.52 (m, 1H),6.32-6.34 (m, 2H), 5.85 (s, 2H), 5.02 (s, 2H), 4.74-4.77 (m, 1H),4.56-4.62 (m, 1H), 3.37-4.16 (m, 7H), 1.14 (t, J=7.10 Hz, 3H).

LCMS: (Method B) 421.0 (M+H-TFA), RT 3.49 min, 90.91% (Max), 91.70% (220nm).

HPLC: (Method B) RT 3.60 min, 93.91% (Max), 93.29% (254 nm).

Compound No. 77

400 MHz, DMSO-d6: δ 8.09 (s, 1H), 7.14-7.18 (m, 1H), 6.75-6.84 (m, 3H),6.26 (s, 1H), 5.21-5.40 (m, 2H), 5.08 (s, 2H), 4.68-4.72 (m, 1H),4.46-4.52 (m, 1H), 4.02 (s, 1H), 3.74-3.81 (m, 2H), 3.17-3.31 (m, 3H),2.27 (s, 3H), 1.07 (t, J=7.12 Hz, 3H).

LCMS: (Method A) 420.0 (M+H), RT 2.98 min, 98.18% (Max), 98.30% (220nm).

HPLC: (Method A) RT 2.98 min, 97.94% (Max), 97.94% (220 nm).

Compound No. 78

400 MHz, DMSO-d6: δ 8.11 (s, 1H), 7.29-7.33 (m, 1H), 6.99-7.15 (m, 3H),6.20 (s, 1H), 5.33-5.42 (m, 2H), 5.15 (s, 2H), 4.67-4.71 (m, 1H),4.44-4.50 (m, 1H), 3.98-4.01 (m, 1H), 3.71-3.82 (m, 2H), 3.14-3.15 (m,2H), 1.03 (t, J=7.16 Hz, 3H).

LCMS: (Method A) 440.0 (M+H), RT 3.10 min, 99.03% (Max), 99.09% (220nm).

HPLC: (Method A) RT 3.23 min, 97.75% (Max), 97.80% (220 nm).

Compound No. 79

400 MHz, DMSO-d6: δ 8.13 (s, 1H), 7.29-7.35 (m, 1H), 6.85-6.96 (m, 1H),6.75-6.80 (m, 2H), 6.23 (s, 1H), 5.23-5.39 (m, 2H), 5.14 (s, 2H),4.67-4.72 (m, 1H), 4.49-4.51 (m, 1H), 3.99-4.01 (m, 1H), 3.74-3.81 (m,2H), 3.15-3.35 (m, 3H), 1.06 (s, 3H).

LCMS: (Method A) 424.3 (M+H), RT. 2.80 min, 97.86% (Max), 97.89% (220nm).

HPLC: (Method A) RT 2.94 min, 97.98% (Max), 97.64% (220 nm).

Compound No. 80

400 MHz, DMSO-d6: δ 8.09 (s, 1H), 7.16-7.20 (m, 1H), 6.51-6.62 (m, 3H),6.19 (s, 1H), 5.25-5.30 (m, 2H), 5.09 (s, 2H), 4.66-4.70 (m, 1H),4.44-4.49 (m, 1H), 3.97-4.00 (m, 1H), 3.75-3.81 (m, 2H), 3.72 (s, 3H),3.12-3.31 (m, 3H), 1.06 (t, J=7.16 Hz, 3H).

LCMS: (Method A) 436.0 (M+H), RT 2.69 min, 97.54% (Max), 97.45% (220nm).

HPLC: (Method A) RT 2.72 min, 97.47% (Max), 97.85% (220 nm).

Compound No. 81

400 MHz, DMSO-d6: δ 8.21 (s, 1H), 7.38-7.60 (m, 4H), 6.13 (d, J=6.24 Hz,1H), 5.24 (s, 3H), 4.66-4.70 (m, 1H), 4.43-4.48 (m, 1H), 3.69-3.82 (m,3H), 3.56 (s, 1H), 3.08-3.32 (m, 6H), 1.03 (t, J=7.20 Hz, 3H).

LCMS: (Method A) 484.0 (M+H), RT 2.16 min, 97.59% (Max), 97.27% (220nm).

HPLC: (Method A) RT 2.14 min, 97.49% (Max), 97.73% (220 nm).

Compound No. 82

400 MHz, DMSO-d6: δ 10.39 (s, 1H), 10.06 (s, 1H), 8.22 (s, 1H),7.46-7.74 (m, 4H), 7.09-7.13 (m, 1H), 6.50-6.52 (m, 1H), 5.84 (s, 2H),5.33 (s, 2H), 4.77-4.80 (m, 1H), 4.58-4.64 (m, 1H), 3.35-4.16 (m, 5H),1.14 (t, J=7.11 Hz, 3H).

LCMS: (Method A) 431.3 (M+H), RT 2.55 min, 97.92% (Max), 97.59% (220nm).

HPLC: (Method A) RT 2.56 min, 97.37% (Max), 97.39% (220 nm).

Compound No. 102

400 MHz, DMSO-d6: δ 10.54 (s, 1H), 10.17 (s, 1H), 8.13-8.22 (m, 4H),6.99-7.41 (m, 4H), 6.52 (d, J=6.28 Hz, 1H), 5.89 (s, 2H), 5.25 (s, 2H),4.74-4.79 (m, 1H), 4.56-4.61 (m, 1H), 3.81-4.14 (m, 5H), 1.16 (t, J=7.12Hz, 3H).

LCMS: (Method A) 435.3 (M+H), RT 1.69 min, 95.12% (Max), 95.13% (220nm).

HPLC: (Method A) RT 1.70 min, 96.42% (Max), 96.51% (220 nm).

Compound No. 83

400 MHz, DMSO-d6: δ 8.57 (s, 1H), 8.21 (s, 1H), 7.29-7.42 (m, 3H),7.02-7.05 (m, 1H), 6.51-6.57 (m, 1H), 5.99 (s, 1H), 5.87 (s, 1H), 5.26(d, J=3.36 Hz, 2H), 4.60-4.80 (m, 2H), 4.06-4.27 (m, 3H), 2.52-2.58 (m,2H), 1.16 (t, J=7.13 Hz, 3H).

LCMS: (Method A) 449.3 (M+H), RT 1.81 min, 94.91% (Max), 95.54% (220nm).

HPLC: (Method A) RT 1.79 min, 94.46% (Max), 94.54% (220 nm).

Compound No. 84

400 MHz, DMSO-d6: δ 9.02 (s, 1H), 8.11 (s, 1H), 6.71-7.06 (m, 4H), 6.19(d, J=5.48 Hz, 1H), 5.11-5.31 (m, 2H), 5.09 (s, 2H), 4.66-4.70 (m, 1H),4.44-4.50 (m, 1H), 3.97-4.00 (m, 1H), 3.41-3.82 (m, 3H), 3.14 (q, J=7.04Hz, 2H), 1.05 (t, J=6.80 Hz, 3H).

LCMS: (Method A) 422.0 (M+H), RT 2.23 min, 95.82% (Max), 96.66% (220nm).

HPLC: (Method A) RT 2.20 min, 96.51% (Max), 96.26% (220 nm).

Compound No. 85

400 MHz, DMSO-d6: δ 8.08 (s, 1H), 8.06 (s, 1H), 7.42-7.44 (m, 1H),6.92-7.20 (m, 3H), 6.92-6.96 (m, 1H), 6.16 (d, J=5.04 Hz, 1H), 5.13-5.41(m, 4H), 4.93-4.96 (m, 2H), 4.67-4.71 (m, 1H), 4.46-4.48 (m, 1H),3.11-4.21 (m, 6H), 1.22 (d, J=6.04 Hz, 3H), 1.04 (t, J=7.08 Hz, 3H).

LCMS: (Method A) 450.3 (M+H), RT 2.35 min, 95.58% (Max), 95.57% (220nm).

HPLC: (Method A) RT 2.47 min, 97.29% (Max), 97.24% (220 nm).

Compound No. 86

400 MHz, DMSO-d6: δ 8.11 (s, 1H), 7.29-7.43 (m, 3H), 6.94-6.99 (m, 1H),6.53 (s, 1H), 6.15-6.17 (m, 1H), 5.22-5.41 (m, 4H), 4.67-4.71 (m, 1H),4.47-4.49 (m, 1H), 3.96-3.98 (m, 1H), 3.80-3.82 (m, 1H), 3.38 (s, 1H),3.12 (q, J=6.68 Hz, 2H), 1.04 (t, J=7.16 Hz, 3H).

LCMS: (Method A) 440.0 (M+H), RT 2.94 min, 98.26% (Max), 98.21% (220nm).

HPLC: (Method A) RT 3.10 min, 98.12% (Max), 98.13% (220 nm).

Compound No. 87

400 MHz, DMSO-d6: δ 8.07 (s, 1H), 7.09-7.17 (m, 3H), 6.83-6.87 (m, 1H),6.15 (s, 1H), 5.12-5.34 (m, 4H), 4.67-4.70 (m, 1H), 4.42-4.48 (m, 1H),3.98-4.01 (m, 1H), 3.80-3.83 (m, 1H), 3.70-3.72 (m, 1H), 3.32 (s, 1H),2.11 (s, 3H), 1.04 (t, J=7.12 Hz, 3H).

LCMS: (Method A) 420.3 (M+H), RT 2.96 min, 98.43% (Max), 98.19% (220nm).

HPLC: (Method A) RT 2.98 min, 97.54% (Max), 97.51% (220 nm).

Compound No. 88

400 MHz, DMSO-d6: δ 8.10 (s, 1H), 6.86-7.12 (m, 4H), 6.17 (s, 1H),5.13-5.31 (m, 2H), 5.07 (s, 2H), 4.66-4.70 (m, 1H), 4.43-4.49 (m, 1H),3.72-3.98 (m, 6H), 3.35-3.36 (m, 1H), 3.13 (q, J=7.16 Hz, 2H), 1.04 (t,J=7.16 Hz, 3H).

LCMS: (Method A) 436.0 (M+H), RT 2.52 min, 98.68% (Max), 98.77% (220nm).

HPLC: (Method A) RT 2.49 min, 98.98% (Max), 98.82% (220 nm).

Compound No. 89

400 MHz, DMSO-d6: δ 8.13 (s, 1H), 7.11-7.36 (m, 4H), 6.12-6.14 (m, 1H),5.19-5.21 (m, 2H), 4.66-4.70 (m, 1H), 4.42-4.48 (m, 1H), 3.69-4.12 (m,3H), 3.10-3.12 (m, 2H), 1.03 (t, J=7.12 Hz, 3H).

LCMS: (Method A) 424.0 (M+H), RT 2.70 min, 96.44% (Max), 96.59% (220nm).

HPLC: (Method A) RT 2.71 min, 98.53% (Max), 98.49% (220 nm).

Compound No. 90

400 MHz, DMSO-d6: δ 8.10 (s, 1H), 7.24 (d, J=8.52 Hz, 2H), 6.95 (q,J=8.72 Hz, 2H), 6.29 (s, 1H), 5.48-5.61 (m, 2H), 5.09 (s, 2H), 5.01-5.02(m, 1H), 4.64-4.72 (m, 3H), 4.47-4.53 (m, 1H), 4.02-4.05 (m, 2H), 3.35(s, 1H), 3.19-3.21 (m, 2H), 1.29 (d, J=6.22 Hz, 3H), 1.03 (t, J=7.20 Hz,3H).

LCMS: (Method A) 450.0 (M+H), RT 2.14 min, 91.11% (Max), 93.37% (220nm).

HPLC: (Method A) RT 2.14 min, 94.18% (Max), 94.06% (220 nm).

Compound No. 91

400 MHz, DMSO-d6: δ 8.13 (s, 1H), 8.07 (s, 1H), 7.08 (d, J=8.24 Hz, 2H),6.90 (d, J=8.60 Hz, 2H), 6.18 (s, 1H), 5.26-5.33 (m, 2H), 4.43-4.69 (m,2H), 3.97-3.99 (m, 1H), 3.70-3.82 (m, 2H), 3.11-3.17 (m, 2H), 2.22 (s,3H), 1.05 (t, J=7.16 Hz, 3H).

LCMS: (Method A) 420.0 (M+H), RT 2.97 min, 98.63% (Max), 98.27% (220nm).

HPLC: (Method A) RT 3.06 min, 98.62% (Max), 98.64% (220 nm).

Compound No. 92

400 MHz, DMSO-d6: δ 8.10 (s, 1H), 7.31-7.34 (m, 2H), 7.04-7.07 (m, 2H),6.19 (s, 1H), 5.30-5.39 (m, 2H), 5.12 (s, 2H), 4.66-4.70 (m, 1H),4.44-4.49 (m, 1H), 3.98-4.01 (m, 1H), 3.70-3.82 (m, 1H), 3.12-3.15 (m,2H), 1.07 (t, J=7.18 Hz, 3H).

LCMS: (Method A) 440.0 (M+H), RT 3.11 min, 96.14% (Max), 97.82% (220nm).

HPLC: (Method A) RT 3.13 min, 98.16% (Max), 98.14% (220 nm).

Compound No. 93

400 MHz, DMSO-d6: δ 8.09 (s, 1H), 7.02-7.14 (m, 4H), 6.20 (s, 1H),5.21-5.50 (m, 2H), 5.12 (s, 2H), 4.66-4.70 (m, 1H), 4.44-4.49 (m, 1H),3.99-4.00 (m, 1H), 3.70-3.32 (m, 3H), 3.14-3.16 (m, 2H), 1.05 (t, J=7.16Hz, 3H).

LCMS: (Method A) 424.3 (M+H), RT 2.73 min, 99.27% (Max), 99.37% (220nm).

HPLC: (Method A) RT 2.76 min, 99.26% (Max), 99.03% (220 nm).

Compound No. 94

400 MHz, DMSO-d6: δ 8.08 (s, 1H), 7.29 (dd, J=2.16, 6.74 Hz, 2H), 6.94(dd, J=2.12, 6.72 Hz, 2H), 6.19 (s, 1H), 5.28 (s, 2H), 5.08 (s, 2H),4.66-4.69 (m, 1H), 4.44-4.49 (m, 1H), 3.73-3.99 (m, 3H), 3.32-0.00 (m,1H), 3.16-0.00 (m, 2H), 1.24 (s, 9H), 1.05 (t, J=7.24 Hz, 3H).

LCMS: (Method A) 462.3 (M+H), RT 3.87 min, 98.04% (Max), 98.10% (220nm).

HPLC: (Method A) RT 3.86 min, 97.12% (Max), 97.35% (220 nm).

EXAMPLE 48(3aR,5S,6S,7R,7aR)-2-(ethylamino)-6,7-dihydroxy-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-5-carboxylicacid

The carboxylic acid intermediate of Schemes 1 to 3 was synthesized asfollows: To a suspension of(3aR,5R,6S,7R,7aR)-2-(ethylamino)-5-(hydroxymethyl)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazole-6,7-diol(23 g, 93 mmol) in 1:1 THF/aqueous NaHCO₃ (1200 mL) was added TEMPO (3.2g, 20 mmol) and potassium bromide (3.5 g, 30 mmol). The mixture was thencooled to 0° C. and a solution of sodium hypochlorite (190 mL, 9% activechlorine basis) was added, dropwise. After 1 h, additional amounts ofsodium hypochlorite solution (95 mL) and TEMPO (1.6 g, 10 mmol) wereadded. After TLC analysis indicated the reaction was complete, thereaction solution was extracted with diethyl ether (2×250 mL). Theaqueous layer was acidified with 5N HCl to pH 5-6, and then concentratedunder reduced pressure. The residue was purified by flash chromatographyon silica gel using a gradient of methanol/dichloromethane (1% to 50%)to afford the title compound (23 g).

MS (m/z): 263 [M+H]⁺.

EXAMPLE 49 Human O-GlcNAcase enzyme inhibition assay

A TTP LabTech Mosquito liquid handler instrument pipetted 100 nL of theappropriate concentration of a solution of inhibitor in 100% DMSO (for adose response curve calculation) into each well of a 384-well plate(Aurora Biotechnologies, Part #30311). The following reaction componentswere added to a final volume of 104 in McIlvaine's Buffer (pH 6.5): 20nM His-Tagged hOGA and 10 μM Fluorosceinmono-beta-D-(2-deoxy-2-N-acetyl)glucopyranoside (FL-GlcNAc; Marker GeneTechnologies Inc, Part # M1485). The plate was incubated for 60 min atroom temperature and then the reaction was terminated by the addition of10 μL of stop buffer (200 mM glycine, pH 10.75). The plate was read onan Envision platform in a fluorescent format using the top mirror with485 nm+dampener as the excitation filter setting and 520 nm as theemission filter setting. The amount of fluorescence measured was plottedagainst the concentration of inhibitor to produce a sigmoidal doseresponse curve, from which an IC₅₀ was calculated.

EXAMPLE 50 Assay for the Determination of Cellular Activity forCompounds that Inhibit O-GlcNAcase Activity

Inhibition of O-GlcNAcase, which removes O-GlcNAc from cellularproteins, results in an increase in the level of O-GlcNAcylated proteinsin cells. An increase in the O-GlcNAcylation of cellular proteins can bemeasured by an antibody, such as CTD110.6, that binds O-GlcNAcylatedproteins. The amount of O-GlcNAcylated protein can be determined by theenzyme linked immunoabsorbant assay (ELISA) technique.

Cell lines, such as rat B35, rat PC-12 and human SH-SY5Y cells,expressing endogenous levels of O-GlcNAcase, could be utilized. Cellswere plated in 96-well plates at a density of approximately 10,000cells/well. Compounds to be tested were dissolved in DMSO as 10 mM stocksolution, and then diluted first with DMSO and then culture media usingthe Bravo workstation. Cells were treated with diluted compounds forapproximately 16 hours. Typically, eight 4-fold dilutions steps,starting at 25 μM were used to reach a final concentration of inhibitordesired to measure a compound concentration dependent response in cells.To prepare a cell lysate, the media from compound treated cells wereremoved, and the cells were washed once with Dulbecco's phosphatebuffered saline (DPBS) and then lysed for 30 minutes in 100 μl/well ofice cold RIPA buffer containing a protease inhibitor cocktail.

The ELISA portion of the assay was performed in EIA/RIA plates that werecoated overnight at 4 C with 80 μl/well of cell lysate. The followingday the wells were washed 6 times with 200 μl of wash buffer (0.05%Tween20 in DPBS). The wells were blocked with 200 μl blocking buffer (1%BSA, 0.05% Tween20 in DPBS) for 1 h at room temperature. Each well wasthen washed 6 times with 200 μl of wash buffer. The anti-O-GlcNAcantibody CTD110.6 (Covance, Princeton, N.J.) was added at 100 μl/well ata concentration of 10 μg/ml. The plates were incubated for 1 h at roomtemperature. The wells were then washed 6 times with 200 μl/well of washbuffer. To detect the amount of CTD110.6 bound to the cell lysate,alkaline phosphatase conjugated goat anti-mouse IgM (diluted 1:500 inblocking buffer) was added at 100 μl/well and incubated for 45 min atroom temperature. Each well was then washed 6 times with 200 μl/well ofwash buffer. PNPP tablets dissolved in diethanolamine substrate bufferand 100 μl/well were added as detection reagent. The detection reactionwas incubated for 25 min at room temperature and absorbance was read at405 nm.

The amount of O-GlcNAcylated protein, as detected by the ELISA assay,was plotted for each concentration of test compound using standard curvefitting algorithms for sigmoidal dose response curves. The values for afour parameter logistic curve fit of the data were determined, with theinflection point of the curve being the potency value for the testcompound.

EXAMPLE 51 Pharmaceutical Preparations

(A) Injection vials: A solution of 100 g of an active ingredientaccording to the invention and 5 g of disodium hydrogen phosphate in 3 lof bi-distilled water was adjusted to pH 6.5 using 2 N hydrochloricacid, sterile filtered, transferred into injection vials, lyophilizedunder sterile conditions and sealed under sterile conditions. Eachinjection vial contained 5 mg of active ingredient.

(B) Suppositories: A mixture of 20 g of an active ingredient accordingto the invention was melted with 100 g of soy lecithin and 1400 g ofcocoa butter, poured into moulds and allowed to cool. Each suppositorycontained 20 mg of active ingredient.

(C) Solution: A solution was prepared from 1 g of an active ingredientaccording to the invention, 9.38 g of NaH₂PO₄.2 H₂O, 28.48 g ofNa₂HPO₄.12 H₂O and 0.1 g of benzalkonium chloride in 940 ml ofbi-distilled water. The pH was adjusted to 6.8, and the solution wasmade up to 11 and sterilized by irradiation. This solution could be usedin the form of eye drops.

(D) Ointment: 500 mg of an active ingredient according to the inventionwere mixed with 99.5 g of Vaseline under aseptic conditions.

(E) Tablets: A mixture of 1 kg of an active ingredient according to theinvention, 4 kg of lactose, 1.2 kg of potato starch, 0.2 kg of talc and0.1 kg of magnesium stearate was pressed to give tablets in aconventional manner in such a way that each tablet contained 10 mg ofactive ingredient.

(F) Coated tablets: Tablets were pressed analogously to EXAMPLE E andsubsequently coated in a conventional manner with a coating of sucrose,potato starch, talc, tragacanth and dye.

(G) Capsules: 2 kg of an active ingredient according to the inventionwere introduced into hard gelatin capsules in a conventional manner insuch a way that each capsule contained 20 mg of the active ingredient.

(H) Ampoules: A solution of 1 kg of an active ingredient according tothe invention in 601 of bi-distilled water was sterile filtered,transferred into ampoules, lyophilized under sterile conditions andsealed under sterile conditions. Each ampoule contained 10 mg of activeingredient.

(I) Inhalation spray: 14 g of an active ingredient according to theinvention were dissolved in 10 l of isotonic NaCl solution, and thesolution was transferred into commercially available spray containerswith a pump mechanism. The solution could be sprayed into the mouth ornose. One spray shot (about 0.1 ml) corresponded to a dose of about 0.14mg.

1. A method for treating a condition selected from the group ofneurodegenerative diseases, diabetes, cancer and stress, said methodcomprising administering an effective amount of at least one compound offormula (I)

wherein R¹ denotes Y, COA, COOA, COO—(CH₂)_(n)—Ar or COO—(CH₂)_(n)-Cyc;R², R³ denote independently from one another Y or SO₂Y; R⁴ denotes Cl,Br, I, COOY, SO₂Y, CN, CAr₃, (CH₂)_(m)—Ar,

R⁵ denotes (CH₂)_(n)—Ar, (CH₂)_(n)-Cyc, (CH₂)_(n)-Het, (CH₂)_(n)—O—Ar,(CH₂)_(n)—CY(OH)—Ar, (CH₂)_(n)—CO—Ar or (CH₂)_(n)—NY—Ar; X denotes CH₂,CO or CH(OH); Y denotes H or A; A denotes unbranched or branched alkylhaving 1-10C atoms, in which 1-7H atoms can be replaced independentlyfrom one another by Hal or in which one CH₂ group can be replaced by a—CH═CH— group; Cyc denotes cycloalkyl having 3-7C atoms, in which 1-4Hatoms can be replaced independently from one another by Hal or which canbe substituted by Ar; Ar denotes an unsaturated or aromatic mono- orbicyclic carbocycle having 3-12C atoms, which can be substituted by atleast one substituent selected from the group of Hal, A, (CY₂)_(n)—OY,(CY₂)_(n)—NYY, COOY, CONYY, NHCOY, SO₂Y, CN and phenoxy; Het denotes anunsaturated or aromatic mono-, bi- or tricyclic heterocycle having 1-12Catoms and 1-4 N atoms, which can be substituted by at least onesubstituent selected from the group of Hal, A, (CY₂)_(n)—OY,(CY₂)_(n)—NYY, COOY, CONYY, NHCOY, SO₂Y, SO₂Ar, CN and thiophenyl; Haldenotes F, Cl, Br or I; m denotes 1, 2 or 3; and n denotes 0, 1, 2, 3,4, 5 or 6; or a physiologically acceptable salt thereof to a mammal inneed of such treatment.
 2. The method according to claim 1, wherein thecondition is selected from the group of tauopathy, Amyotrophic lateralsclerosis (ALS), Amyotrophic lateral sclerosis with cognitive impairment(ALSci), Argyrophilic grain dementia, Bluit disease, Corticobasaldegeneration (CBP), Dementia pugilistica, Diffuse neurofibrillarytangles with calcification, Down's syndrome, Familial British dementia,Familial Danish dementia, Frontotemporal dementia with parkinsonismlinked to chromosome 17 (FTDP-17), Gerstmann-Straussler-Scheinkerdisease, Guadeloupean parkinsonism, Hallevorden-Spatz disease(neurodegeneration with brain iron accumulation type 1), Multiple systematrophy, Myotonic dystrophy, Niemann-Pick disease (type C),Pallido-ponto-nigral degeneration, Parkinsonism-dementia complex ofGuam, Pick's disease (PiD), Postencephalitic parkinsonism (PEP), Priondiseases (including Creutzfeldt-Jakob Disease (GJD), VariantCreutzfeldt-Jakob Disease (vCJD), Fatal Familial Insomnia, Kuru,Progressive supercortical gliosis, Progressive supranuclear palsy (PSP),Richardson's syndrome, Subacute sclerosing panencephalitis, Tangle-onlydementia, Huntington's disease and Parkinson's disease.
 3. The methodaccording to claim 1 for treating a tauopathy.
 4. The method accordingto claim 1, wherein the condition is selected from the group ofProgressive supranuclear palsy (PSP), Frontotemporal dementia withparkinsonism linked to chromosome 17 (FTDP-17), Corticobasaldegeneration (CBP) and Pick's disease (PiD).
 5. The method according toclaim 1, wherein R¹, R², R³ denote independently from one another H orA.
 6. The method according to claim 5, wherein R¹, R², R³ denote H. 7.The method according to claim 1, wherein R⁵ denotes (CH₂)_(n)—Ar,(CH₂)_(n)-Cyc, (CH₂)_(n)-Het, (CH₂)_(n)—O—Ar or CY(OH)—Ar.
 8. The methodaccording to claim 1, administering sub-formula (IA), (IB) or (IC)

wherein R⁶ denotes Cl, Br, I, COOY, CAr₃ or

R⁷ denotes (CH₂)_(m)—Ar or

R⁸ denotes (CH₂)_(m)—Ar; and R¹, R², R³, R⁵, Y, Ar, Het, m and n havethe meaning as defined in claim 1; or a physiologically acceptable saltthereof.
 9. The method according to claim 8, administering sub-formula(IA-1) or (IA-2)

wherein Hal denotes Cl, Br or I; and R⁵ and Y have the meaning asdefined in claim 8; or a physiologically acceptable salt thereof. 10.The method according to claim 1, wherein A denotes unbranched orbranched alkyl having 1-6C atoms, in which 1-4H atoms can be replacedindependently from one another by Hal; Ar denotes an aromatic mono- orbicyclic carbocycle having 3-12C atoms, which can be substituted by atleast one substituent selected from the group of Hal, A, (CY₂)_(n)—OY,(CY₂)_(n)—NYY, SO₂Y, CN and phenoxy; Het denotes an unsaturated oraromatic mono-, bi- or tricyclic heterocycle having 2-12C atoms and 1-3N atoms, which can be mono-, di- or trisubstituted by at least onesubstituent selected from the group of Hal, A, (CH₂)_(n)—OY,(CY₂)_(n)—NYY, SO₂Y, SO₂Ar, CN and thiophenyl; or n denotes 0, 1, 2, 3or
 4. 11. The method according to claim 1, wherein the compound isselected from the group consisting of:

or a physiologically acceptable salt thereof.